Method for producing optically active compound

ABSTRACT

wherein each symbol is as defined in the specification.

TECHNICAL FIELD

The present invention relates to a production method of an opticallyactive amine compound which is useful for producing an optically activepyrimidinamide derivative, and a production method of an opticallyactive pyrimidinamide derivative using the optically active aminecompound.

BACKGROUND OF THE INVENTION

The pyrimidinamide derivative represented by the below-mentioned formula(V) is known as a Raf protein kinase inhibitor and a therapeutic drugfor cancer and the like.

The following method is known as a production method of the opticallyactive form.

Patent Document 1 discloses that an optically active form of an aminecompound represented by the below-mentioned formula (III) is produced bysubjecting the corresponding ketone compound successively to oximation,reduction, and optical resolution with di-p-toluoyl-(D)-tartaric acid,and the objective optically active form of a pyrimidinamide derivativerepresented by the below-mentioned formula (V) is produced from theoptically active amine compound.

As a production method of an optically active amine compound, non-PatentDocument 1 discloses a reductive asymmetric amination reaction of anaryl acetone with benzhydrylamine using an iridium complex as acatalyst, and non-Patent Document 2 discloses an asymmetric reductionreaction of a compound having a diphenylmethylimino group.

Document List Patent Document

-   [Patent Document 1] WO 2009/006389

Non-Patent Document

-   [Non-Patent Document 1] Huang et al., Angew. Chem. int. Ed. (2016),    55, 5309-5317-   [Non-Patent Document 2] Jiang Xiao-bin et al., Org. Lett. (2003), 5,    1503

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The aim of the present invention is to provide a method capable ofproducing an optically active pyrimidinamide derivative on an industrialscale.

In order to produce an optically active form of an amine compoundrepresented by the below-mentioned formula (III), which is necessary forthe production of an optically active form of a pyrimidinamidederivative represented by the below-mentioned (V), by asymmetricreduction of the corresponding imino compound, it is important that anappropriate protecting group is introducted into the imino compound, andthat the asymmetric reduction reaction is developed.

The diphenylmethyl group as a protecting group is previouslylittle-known. In the method of Non-Patent Document 1, the opticallyactive compound having a diphenylmethylamino group is obtained as aproduct of the reductive asymmetric amination reaction, which isextremely different in structure from an optically active form of anamine compound represented by the below-mentioned formula (II). In themethod of Non-Patent Document 2, the asymmetric reduction reaction ofthe compound having a diphenylmethylimino group results in extremely lowyield and low enantioselectivity.

Means of Solving the Problems

The present inventors have conducted intensive studies to solve theabove-mentioned problems, and have found that, by subjecting an iminocompound having an appropriate protecting group (which is represented bythe below-mentioned formula (I), or a salt thereof) to an asymmetricreduction reaction, followed by deprotection, an optically active formof an amine compound represented by the below-mentioned formula (III) ora salt thereof (which is a key intermediate) can be produced with goodoptical purity in good yield, and therefore, an optically active form ofa pyrimidinamide derivative represented by the below-mentioned formula(V) (which is an objective compound) can be produced on an industrialscale, and completed the present invention based on these findings.

Accordingly, the present invention provides the following.

[1] A method of producing an optically active form of a compoundrepresented by the following formula (II):

whereinR¹ is a C₁₋₆ alkyl group;R² is a hydrogen atom or a halogen atom;R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkyl group;PG is a protecting group; andthe carbon atom marked with * is an asymmetric carbon atom (hereinafter,the optically active form of the compound represented by the formula(II) is to be referred to as compound (II)),or a salt thereof, which comprises subjecting a compound represented bythe following formula (I):

wherein each symbol is as defined above (hereinafter to be referred toas compound (I)),or a salt thereof, to an asymmetric reduction reaction.[2] A method of producing an optically active form of a compoundrepresented by the following formula (V):

whereinR¹ is a C₁₋₆ alkyl group;R² is a hydrogen atom or a halogen atom;R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkyl group;R⁴ and R⁵ are each independently a hydrogen atom, a halogen atom, acyano group, a nitro group, an optionally substituted hydrocarbon group,an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl (SH) group, or an optionally substitutedsilyl group; andthe carbon atom marked with * is an asymmetric carbon atom (hereinafter,the optically active form of the compound represented by the formula (V)is to be referred to as compound (V)),or a salt thereof, which comprises a step of subjecting a compoundrepresented by the following formula (I);

whereinPG is a protecting group, andand the other symbols are as defined above,or a salt thereof, to an asymmetric reduction reaction to obtain anoptically active form of a compound represented by the following formula(II);

wherein each symbol is as defined above,or a salt thereof.[3] The method of the above-mentioned [2], which further comprisesa step of subjecting an optically active form of a compound representedby the following formula (II);

whereinR¹ is a C₁₋₆ alkyl group;R² is a hydrogen atom or a halogen atom;R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkyl group;PG is a protecting group; andthe carbon atom marked with * is an asymmetric carbon atom, or a saltthereof, to a deprotection reaction, anda step of reacting the obtained optically active form of a compoundrepresented by the following formula (III);

wherein each symbol is as defined above (hereinafter, the opticallyactive form of the compound represented by the formula (III) is to bereferred to as compound (III)), or a salt thereof, with a compoundrepresented by the following formula (IV);

whereinX is a leaving group; andR⁴ and R⁵ are each independently a hydrogen atom, a halogen atom, acyano group, a nitro group, an optionally substituted hydrocarbon group,an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl (SH) group, or an optionally substitutedsilyl group (hereinafter to be referred to as compound (IV)),or a salt thereof.[4] The method of the above-mentioned [3], wherein the optically activeform of the compound represented by the formula (III) or a salt thereofis a salt of the optically active form of the compound represented bythe formula (III) with mandelic acid.[5] The method of the above-mentioned [3] or [4], wherein X is a hydroxygroup.[6] The method of any one of the above-mentioned [1] to [5], wherein theasymmetric reduction reaction is an asymmetric hydrogenation reaction inthe presence of a transition metal complex.[7] The method of the above-mentioned [6], wherein the transition metalcomplex is an iridium complex.[8] The method of any one of the above-mentioned [1] to [7], wherein PGis represented by the following formula (VI):

whereinAr¹ is a hydrogen atom or an optionally substituted C₆₋₁₄ aryl group;andAr² is an optionally substituted C₆₋₁₄ aryl group.[9] The method of the above-mentioned [8], wherein Ar¹ and Ar² are eachindependently an optionally substituted phenyl group.[10] A compound represented by the following formula (VII):

wherein Ar³ and Ar⁴ are each independently an optionally substitutedC₆₋₁₄ aryl group (hereinafter to be referred to as compound (VII)),or a salt thereof.[11] An optically active form of a compound represented by the followingformula (VIII):

whereinAr⁵ and Ar⁶ are each independently an optionally substituted C₆₋₁₄ arylgroup, andthe carbon atom marked with * is an asymmetric carbon atom (hereinafter,the optically active form of the compound represented by the formula(VIII) is to be referred to as compound (VIII)),or a salt thereof.[12] A method of producing an optically active form of a compoundrepresented by the formula (III) or a salt thereof, which comprisessubjecting a compound represented by the following formula (A-c)

whereinR¹ is a C₁₋₆ alkyl group;R² is a hydrogen atom or a halogen atom; andR³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkyl group(hereinafter, to be referred to as compound (A-c)) or a salt thereof, toan asymmetric reductive amination reaction.[13] The method of the above-mentioned [12], wherein the asymmetricreductive amination reaction is carried out by reacting a compoundrepresented by the formula (A-c) or a salt thereof with an amine sourceand a reducing agent in the presence of an organic metal complex.

Effect of the Invention

According to the present invention, compound (III) or a salt thereof,which is a key intermediate, can be produced with good optical purity ingood yield, by subjecting compound (I) or a salt thereof to anasymmetric reduction reaction, followed by deprotection. Particularly,after the deprotection, by crystallization of the diastereomer salt withoptically active di-p-toluoyl-tartaric acid or optically active mandelicacid, the salt of compound (III) can be produced with better opticalpurity. Therefore, the objective compound (V) or a salt thereof can beproduced on an industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained below in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent group A.

w[Substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group, and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl) (C₆₋₁₄ aryl-carbonyl) amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxy group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from Substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

The definitions of each symbol in the formula (I), formula (II), formula(III), formula (IV), formula (V), formula (VII) and formula (VIII), andthe compounds are explained below in detail.

R¹ is a C₁₋₆ alkyl group, preferably methyl.

R² is a hydrogen atom or a halogen atom, preferably a chlorine atom.

R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkyl group,preferably a fluorinated C₁₋₆ alkyl group, particularly preferablytrifluoromethyl.

PG is a protecting group. Examples of the “protecting group” include

a group represented by the formula (VI-1):

whereinR⁷ is an optionally substituted C₆₋₁₄ aryl group or an optionallysubstituted C₁₋₆ alkoxy group, anda group represented by the formula (VI):

whereinAr¹ is a hydrogen atom or an optionally substituted C₆₋₁₄ aryl group;andAr² is an optionally substituted C₆₋₁₄ aryl group.

Examples of the “substituent” of the “optionally substituted C₆₋₁₄ arylgroup” represented by R⁷ include the above-mentioned “substituents”. Thenumber of the substituents in the “optionally substituted C₆₋₁₄ arylgroup” represented by R⁷ is, for example, 1 to 5, preferably 1 to 3, atsubstitutable position(s). When the number of the substituents is two ormore, the respective substituents may be the same or different.

Examples of the “substituent” of the “optionally substituted C₁₋₆ alkoxygroup” represented by R⁷ include the above-mentioned “substituents”. Thenumber of the substituents in the “optionally substituted C₁₋₆ alkoxygroup” represented by R⁷ is, for example, 1 to 5, preferably 1 to 3, atsubstitutable position(s). When the number of the substituents is two ormore, the respective substituents may be the same or different.

R⁷ is preferably a C₆₋₁₄ aryl group having no substituent or a C₁₋₆alkoxy group having no substituent, more preferably phenyl ortert-butoxy, particularly preferably phenyl.

The substituent of the “optionally substituted C₆₋₁₄ aryl group”represented by Ar¹ or Ar² and a number thereof are similar to thoseexemplified in the above-mentioned “optionally substituted C₆₋₁₄ arylgroup” represented by R⁷. Preferred is a C₁₋₆ alkoxy group, andparticularly preferred is methoxy.

PG is preferably a group represented by the formula (VI). In this case,Ar¹ and Ar² are preferably each independently an optionally substitutedC₆₋₁₄ aryl group, more preferably each independently optionallysubstituted phenyl, further more preferably each independently phenyloptionally substituted by C₁₋₆ alkoxy group(s), particularly preferablyboth phenyl.

As preferable embodiment,

a compound represented by the formula (I) is a compound represented bythe formula (VII):

whereinAr³ and Ar⁴ are each independently an optionally substituted C₆₋₁₄ arylgroup, andan optically active form of a compound represented by the formula (II)is an optically active form of a compound represented by the formula(VIII):

whereinAr⁵ and Ar⁶ are each independently an optionally substituted C₆₋₁₄ arylgroup, andthe carbon atom marked with * is an asymmetric carbon atom.

The substituent of the “optionally substituted C₆₋₁₄ aryl group”represented by Ar³, Ar⁴, Ar⁵ or Ar⁶ and a number thereof are similar tothose exemplified in the above-mentioned “optionally substituted C₆₋₁₄aryl group” represented by R⁷. Preferred is a C₁₋₆ alkoxy group, andparticularly preferred is methoxy.

Ar³ and Ar⁴ are preferably each independently optionally substitutedphenyl, more preferably each independently phenyl optionally substitutedby C₁₋₆ alkoxy group(s), particularly preferably both phenyl.

Ar⁵ and Ar⁶ are preferably each independently optionally substitutedphenyl, more preferably each independently phenyl optionally substitutedby C₁₋₆ alkoxy group(s), particularly preferably both phenyl.

As the most preferable embodiment, a compound represented by the formula(I) is(E)-2-(1-(benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide;and an optically active form of a compound represented by the formula(II) is2-((1R)-1-(benzhydrylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide.

R⁴ and R⁵ are each independently a hydrogen atom, a halogen atom, acyano group, a nitro group, an optionally substituted hydrocarbon group,an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl (SH) group, or an optionally substitutedsilyl group.

Examples of the “optionally substituted hydrocarbon group” representedby R⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted hydrocarbon group”.

Examples of the “optionally substituted heterocyclic group” representedby R⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted heterocyclic group”.

Examples of the “acyl group” represented by R⁴ or R⁵ include thoseexemplified as the above-mentioned “acyl group”.

Examples of the “optionally substituted amino group” represented by R⁴or R⁵ include those exemplified as the above-mentioned “optionallysubstituted amino group”.

Examples of the “optionally substituted carbamoyl group” represented byR⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted carbamoyl group”.

Examples of the “optionally substituted thiocarbamoyl group” representedby R⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted thiocarbamoyl group”.

Examples of the “optionally substituted sulfamoyl group” represented byR⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted sulfamoyl group”.

Examples of the “optionally substituted hydroxy group” represented by R⁴or R⁵ include those exemplified as the above-mentioned “optionallysubstituted hydroxy group”.

Examples of the “optionally substituted sulfanyl (SH) group” representedby R⁴ or R⁵ include those exemplified as the above-mentioned “optionallysubstituted sulfanyl (SH) group”.

Examples of the “optionally substituted silyl group” represented by R⁴or R⁵ include those exemplified as the above-mentioned “optionallysubstituted silyl group”.

R⁴ is preferably a hydrogen atom, a halogen atom, a cyano group, anoptionally substituted hydrocarbon group, an acyl group, or anoptionally substituted hydroxy group, more preferably a hydrogen atom ora halogen atom, particularly preferably a chlorine atom.

R⁵ is preferably a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted hydroxy group, or an optionallysubstituted sulfanyl (SH) group, more preferably a hydrogen atom, or anoptionally substituted amino group, particularly preferably an aminogroup.

Examples of the leaving group represented by X include a halogen atom,an optionally substituted hydroxy group, an azido group, and anoptionally substituted imidazolyl group.

Examples of the “optionally substituted hydroxy group” represented by Xinclude those exemplified as the above-mentioned “optionally substitutedhydroxy group”.

Examples of the substituent of the “optionally substituted imidazolylgroup” represented by X include a C₁₋₆ alkyl group. Preferred is methyl.

X is preferably a hydroxy group.

As the most preferable embodiment,

a compound represented by the formula (IV) is6-amino-5-chloropyrimidine-4-carboxylic acid; andan optically active form of a compound represented by the formula (V) is6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide.

The compound represented by the formula (I), (II), (IV), (V), (VII) or(VIII) may be a salt.

Examples of the salt of the compound represented by the formula (I),(II), (IV), (V), (VII) or (VIII) include metal salts, ammonium salts,salts with an organic base, salts with an inorganic acid, salts with anorganic acid, salts with a basic or acidic amino acid, and the like.

Preferable examples of the metal salt include alkali metal salts such assodium salt, potassium salt and the like; alkaline-earth metal saltssuch as calcium salt, magnesium salt, barium salt and the like;aluminium salt, and the like.

Preferable examples of the salt with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with an inorganic acid include saltswith hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodicacid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid,phosphorous acid, carbonic acid, bicarbonic acid and the like.

Preferable examples of the salt with an organic acid include salts witha carboxylic acid (i.e., an organic compound having one or more carboxygroups; specific examples thereof include formic acid, acetic acid,benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, a tartaric acid derivative, mandelic acid, maleicacid, citric acid, succinic acid, malic acid, and the above-mentionedbasic or acidic amino acid wherein the amino group is protected, and thelike); and a sulfonic acid (i.e., an organic compound having one or moresulfo groups; specific examples thereof include methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid and the like).

Examples of the salt with a tartaric acid derivative include salts withdi-p-toluoyl-tartaric acid, dibenzoyltartaric acid, di-p-anisoyltartaricacid and the like.

Preferable examples of the salt with a basic amino acid include saltswith arginine, lysine, ornithine and the like. Preferable examples ofthe salt with an acidic amino acid include salts with aspartic acid,glutamic acid and the like.

Examples of the protecting group for the basic or acidic amino acidwherein the amino group is protected include ter-butoxycarbonyl, acetyland the like.

The optically active form of the compound represented by the formula(III) is preferably in the form of a salt.

Examples of the salt of the optically active form of the compoundrepresented by the formula (III) include salts with an inorganic acid,salts with an organic acid, salts with a basic or acidic amino acid, andthe like.

Preferable examples of the salt of the optically active form of thecompound represented by the formula (III) with an inorganic acid includethose exemplified as the salt of the compound represented by the formula(I), (II), (IV), (V), (VII) or (VIII) with an inorganic acid.

Preferable examples of the salt of the optically active form of thecompound represented by the formula (III) with an organic acid includethose exemplified as the salt of the compound represented by the formula(I), (II), (IV), (V), (VII) or (VIII) with an organic acid.

Preferable examples of the salt of the optically active form of thecompound represented by the formula (III) with a basic or acidic aminoacid include those exemplified as the salt of the compound representedby the formula (I), (II), (IV), (V), (VII) or (VIII) with a basic oracidic amino acid.

The optically active form of the compound represented by the formula(III) is preferably in the form of a salt, more preferably in the formof a salt with an optically active organic acid or a salt with anoptically active basic or acidic amino acid, further more preferably inthe form of a salt with optically active di-p-toluoyl-tartaric acid(preferably di-p-toluoyl-(D)-tartaric acid when the optically activeform of the compound represented by the formula (III) is (R)-form) or asalt with optically active mandelic acid (preferably (S)-mandelic acidwhen the optically active form of the compound represented by theformula (III) is (R)-form), particularly preferably in the form of asalt with optically active mandelic acid (preferably (S)-mandelic acidwhen the optically active form of the compound represented by theformula (III) is (R)-form).

As the most preferable embodiment, the optically active form of thecompound represented by the formula (III) is2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide;and the optically active form of the compound represented by the formula(V) is6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide.

In the most preferable embodiment, the salt of the optically active formof the compound represented by the formula (III) is a salt with(S)-mandelic acid.

The compound represented by the formula (I), (II), (III), (IV), (V),(VII) or (VIII), or a salt thereof may be each a solvate (e.g., ahydrate, an ethanolate, etc.) or a non-solvate (e.g., a non-hydrate,etc.), which is encompassed in the compound represented by the formula(I), (II), (III), (IV), (V), (VII) or (VIII), or a salt thereof.

The compound labeled with an isotope and the like, or a salt thereof isalso encompassed in the compound represented by the formula (I), (II),(III), (IV), (V), (VII) or (VIII), or a salt thereof.

A deuterium conversion form wherein 1H is converted to ²H(D) is alsoencompassed in the compound represented by the formula (I), (II), (III),(IV), (V), (VII) or (VIII), or a salt thereof.

The production method (Production Method (A)) of compound (III) or asalt thereof, and the production method (Production Method (B)) ofcompound (V) or a salt thereof using compound (III) or a salt thereofobtained in the Production Method (A) are explained below in detail.

[Production Method (A)]

Compound (III) or a salt thereof can be produced according to ProductionMethod (A) shown in the following scheme.

Production Method (A)

wherein X_(A) is a leaving group, and the other symbols are as definedabove.

Examples of the leaving group represented by X_(A) include thoseexemplified as the above-mentioned the leaving group represented by X.

X_(A) is preferably a hydroxy group or a chlorine atom.

The reagent and condition used in each step of Production Method (A) areexplained in detail.

[Step A-1]

Step A-1 is a step of producing a compound represented by the formula(A-c) (hereinafter to be referred to as compound (A-c)) or a saltthereof by a method forming an amide bond from a compound represented bythe formula (A-a) (hereinafter to be referred to as compound (A-a)) or asalt thereof and a compound represented by the formula (A-b)(hereinafter to be referred to as compound (A-b)) or a salt thereof.

Compound (A-a) or a salt thereof may be a commercially availableproduct.

Examples of the salt of compound (A-a) include metal salts, ammoniumsalts, salts with an organic base, salts with a basic amino acid, andthe like.

Preferable examples of the metal salt of compound (A-a) include thoseexemplified as the metal salt of compound (I), (II), (IV), (V), (VII) or(VIII).

Preferable examples of the salt of compound (A-a) with an organic baseinclude those exemplified as the salt of compound (I), (II), (IV), (V),(VII) or (VIII) with an organic base.

Preferable examples of the salt of compound (A-a) with a basic aminoacid include those exemplified as the salt of compound (I), (II), (IV),(V), (VII) or (VIII) with a basic amino acid.

Compound (A-b) can be produced, for example, according to the methoddescribed in WO 2009-006389.

Examples of the salt of compound (A-b) include salts with an inorganicacid, salts with an organic acid, salts with an acidic amino acid, andthe like.

Preferable examples of the salt of compound (A-b) with an inorganic acidinclude those exemplified as the salt of compound (I), (II), (IV), (V),(VII) or (VIII) with an inorganic acid.

Preferable examples of the salt of compound (A-b) with an organic acidinclude those exemplified as the salt of compound (I), (II), (IV), (V),(VII) or (VIII) with an organic acid.

Preferable examples of the salt of compound (A-b) with an acidic aminoacid include those exemplified as the salt of compound (I), (II), (IV),(V), (VII) or (VIII) with an acidic amino acid.

The salt of compound (A-b) is particularly preferably a hydrochloride.

The above-mentioned method “forming an amide bond” can be carried outaccording to a method known per se, such as the method described inTetrahedoron, vol., 61, page 10827, 2005.

The method “forming an amide bond” is preferably a method of producingcompound (A-c) or a salt thereof by condending compound (A-a) whereinX_(A) is a halogen atom (an acid halide) and compound (A-b) or a saltthereof. Among them, a method using compound (A-a) wherein X_(A) is achlorine atom (an acid chloride) is particularly preferable.

For preparation of the acid chloride, the hydroxy group of X_(A) isconverted to a chlorine atom by a method using a chlorinating agent suchas thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorustrichloride, phosphorus pentachloride and the like.

As the “chlorinating agent”, thionyl chloride, oxalyl chloride andphosphorus oxychloride are preferable, and oxalyl chloride isparticularly preferable.

When oxalyl chloride is used as a “chlorinating agent”, the reaction ispreferably carried out in the presence of N,N-dimethylformamide. Theamount of the N,N-dimethylformamide to be used is a catalytic amount,preferably 0.0001 to 0.1 mol, more preferably 0.001 to 0.01 mol, per 1mol of the oxalyl chloride.

While the amount of the oxalyl chloride to be used varies depending onthe kind of the solvent and the other reaction condition, it isgenerally 0.1 to 10 mol, preferably 0.8 to 1.2 mol, per 1 mol of thesubstrate compound (A-a) or a salt thereof.

While the reaction for the preparation of the acid chloride using oxalylchloride as a “chlorinating agent” may be carried out without a solvent,it is generally carried out in a solvent. The solvent is notparticularly limited as long as it does not inhibit the reaction and candissolve the raw material compound and additive, and examples thereofinclude ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane,methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane,1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; halogenated hydrocarbons such as chloroform,dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;nitriles such as acetonitrile, propionitrile and the like; sulfoxidessuch as dimethyl sulfoxide and the like; sulfones such asdimethylsulfone, sulfolane and the like; ketones such as acetone, ethylmethyl ketone, methyl isopropyl ketone, methyl butyl ketone and thelike; nitromethane and the like. These solvents may be used in a mixturein an appropriate ratio. As the solvent used in the reaction for thepreparation of the acid chloride using oxalyl chloride as a“chlorinating agent”, ethers are preferable, and 1,2-dimethoxyethane isparticularly preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate compound (A-a) or a saltthereof, and the like. For example, when an ether (preferably1,2-dimethoxyethane) is used as a solvent, the reaction can be carriedout nearly without a solvent or in a solvent in an amount of 100 partsby weight or less per 1 part by weight of the substrate compound (A-a)or a salt thereof, preferably in a solvent in an amount of 1 to 10 partsby weight per 1 part by weight of the substrate compound (A-a) or a saltthereof.

The temperature in the reaction for the preparation of the acid chlorideusing oxalyl chloride as a “chlorinating agent” is generally −10 to 80°C., preferably 0 to 40° C. The reaction time is generally 0.1 to 12 hr,preferably 0.5 to 4 hr.

The obtained acid chloride of compound (A-a) may be purified accordingto a means known per se (evaporation of low-boiling components such assolvent by concentration, distillation, etc.). Preferably, the reactionsolution is used directly in the condensation reaction with compound(A-b) or a salt thereof.

While the amount of compound (A-b) or a salt thereof to be subjected tothe condensation reaction with the acid chloride of compound (A-a)varies depending on the kind of the solvent and the other reactioncondition, it is generally 0.1 to 10 mol, preferably 0.8 to 1.2 mol, per1 mol of compound (A-a) or a salt thereof.

When the salt of compound (A-b) is used, it is preferably converted tothe free form in advance by reacting with a base, prior to thecondensation reaction with the acid chloride of compound (A-a). Examplesof the base include inorganic bases and organic bases.

Examples of the inorganic base include alkali metal hydroxides such aslithium hydroxide, potassium hydroxide, sodium hydroxide, cesiumhydroxide and the like; alkali metal alkoxides having 1 to 6 carbonatoms such as lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide, lithiumpropoxide, sodium propoxide, potassium propoxide, lithium isopropoxide,sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide andthe like; alkali metal thioalkoxides having 1 to 6 carbon atoms such assodium thiomethoxide and the like; carbonates such as sodium carbonate,potassium carbonate, cesium carbonate and the like; hydrogencarbonatessuch as sodium hydrogencarbonate, potassium hydrogencarbonate and thelike; acetates such as sodium acetate, potassium acetate and the like;phosphates such as tripotassium phosphate, sodium phosphate and thelike; and monohydrogen phosphates such as potassium monohydrogenphosphate, sodium monohydrogen phosphate and the like.

Examples of the organic base include aliphatic amines such astrimethylamine, triethylamine, N-methylmorpholine,N,N-diisopropylethylamine, diethylamine, diisopropylamine,cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene andthe like; aromatic amines such as pyridine, picoline,N,N-dimethylaniline and the like; and basic amino acids such asarginine, lysine, ornithine and the like. These bases may be used in amixture in an appropriate ratio.

As the base for the conversion of the salt of compound (A-b) to the freeform, pyridine is particularly preferable.

While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally 0.1 to 100mol, preferably 0.5 to 20 mol, more preferably 0.8 to 5 mol, per 1 molof the substrate salt of compound (A-b). When the base is a liquid, itcan also be used as a solvent.

While the reaction for the conversion of the salt of compound (A-b) tothe free form may be carried out without a solvent, it is generallycarried out in a solvent. The solvent is not particularly limited aslong as it does not inhibit the reaction and can dissolve the rawmaterial compound and additive, and examples thereof include ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenylether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, t-butyl alcohol,3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.As the solvent used in the reaction for the conversion of the salt ofcompound (A-b) to the free form, nitriles are preferable, andacetonitrile is particularly preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate salt of compound (A-b), andthe like. For example, when a nitrile (preferably acetonitrile) is usedas a solvent, the reaction can be carried out nearly without a solventor in a solvent in an amount of 100 parts by weight or less per 1 partby weight of the substrate salt of compound (A-b), preferably in asolvent in an amount of 1 to 10 parts by weight per 1 part by weight ofthe substrate salt of compound (A-b).

The temperature in the reaction for the conversion to the free form isgenerally −20 to 40° C., preferably −10 to 20° C. The reaction time isgenerally 0.01 to 2 hr, preferably 0.1 to 1 hr.

Compound (A-b) obtained in the reaction for the conversion to the freeform may be isolated and purified according to a means known per se(concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, phase transfer,chromatography and the like). Alternatively, the reaction solution maybe used directly in the condensation reaction with the acid chloride ofcompound (A-a).

The “condensation reaction” is generally carried out in a solvent. Thesolvent is not particularly limited as long as it does not inhibit thereaction and can dissolve the raw material compound and additive, andexamples thereof include ethers such as diethyl ether, diisopropylether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran,1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane,1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisoleand the like; aromatic hydrocarbons such as benzene, toluene, xylene,cumene, chlorobenzene and the like; saturated hydrocarbons such ashexane, heptane, pentane, cyclohexane, methylcyclohexane, isooctane,petroleum ether and the like; halogenated hydrocarbons such aschloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethaneand the like; nitriles such as acetonitrile, propionitrile and the like;sulfoxides such as dimethyl sulfoxide and the like; sulfones such asdimethylsulfone, sulfolane and the like; ketones such as acetone, ethylmethyl ketone, methyl isopropyl ketone, methyl butyl ketone and thelike; nitromethane and the like. These solvents may be used in a mixturein an appropriate ratio. As the solvent used in the above-mentioned“condensation reaction”, ethers are preferable, and 1,2-dimethoxyethaneis particularly preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate acid chloride of compound(A-a) and compound (A-b) or a salt thereof and the like. For example,when an ether (preferably 2-dimethoxyethane) is used as a solvent, thereaction can be carried out nearly without a solvent or in a solvent inan amount of 100 parts by weight or less per 1 part by weight of thesubstrate acid chloride of compound (A-a), preferably in a solvent in anamount of 1 to 10 parts by weight per 1 part by weight of the substrateacid chloride of compound (A-a).

The temperature in the condensation reaction is generally 0 to 120° C.,preferably 10 to 70° C. The reaction time is generally 0.1 to 12 hr,preferably 0.5 to 6 hr.

Compound (A-c) or a salt thereof obtained in the condensation reactionmay be isolated and purified according to a means known per se(concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, phase transfer,chromatography and the like). Compound (A-c) or a salt thereof ispreferably isolated and purified by crystallization, particularlypreferably by crystallization with addition of water.

[Step A-2]

Step A-2 is a step of producing compound (I) or a salt thereof, which isa substrate for asymmetric reduction, by subjecting compound (A-c) or asalt thereof to imination.

When PG is a group represented by the formula (VI-1), compound (A-c) ora salt thereof is reacted with a compound represented by the formula(VI-1′):

wherein each symbol is as defined above (hereinafter to be referred toas compound (VI-1′)) or a salt thereof.

When PG is a group represented by the formula (VI), compound (A-c) or asalt thereof is reacted with a compound represented by the formula(VI′):

wherein each symbol is as defined above (hereinafter to be referred toas compound (VI′)) or a salt thereof.

Examples of the salt of compound (VI-1′) or compound (VI′) include saltswith an inorganic acid, salts with an organic acid, salts with an acidicamino acid, and the like.

Preferable examples of the salt of compound (VI-1′) or compound (VI′)with an inorganic acid include those exemplified as the salt of compound(I), (II), (IV), (V), (VII) or (VIII) with an inorganic acid.

Preferable examples of the salt of compound (VI-1′) or compound (VI′)with an organic acid include those exemplified as the salt of compound(I), (II), (IV), (V), (VII) or (VIII) with an organic acid.

Preferable examples of the salt of compound (VI-1′) or compound (VI′)with an acidic amino acid include those exemplified as the salt ofcompound (I), (II), (IV), (V), (VII) or (VIII) with an acidic aminoacid.

While the amount of compound (VI-1′) or a salt thereof, or compound(VI′) or a salt thereof to be used varies depending on the kind of thesolvent and the other reaction condition, it is generally 0.1 to 100mol, preferably 0.5 to 20 mol, more preferably 0.8 to 5 mol, per 1 molof compound (A-c) or a salt thereof. When compound (VI-1′) or compound(VI′) is a liquid, it can also be used as a solvent.

When the salt of compound (VI-1′) or compound (VI′) is used, it isprepreably converted to the free form in advance by reacting with a baseor acid.

In the reaction of Step A-2, an additive such as a base, an acid, a saltand the like may be added, if necessary. The additive may be used in amixture of two or more kinds thereof. The additive may be added to areaction container before or during the reaction.

Examples of the base which may be added to the reaction system of StepA-2 include inorganic bases and organic bases.

Examples of the inorganic base include alkali metal hydroxides such aslithium hydroxide, potassium hydroxide, sodium hydroxide, cesiumhydroxide and the like; alkali metal alkoxides having 1 to 6 carbonatoms such as lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide, lithiumpropoxide, sodium propoxide, potassium propoxide, lithium isopropoxide,sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide andthe like; alkali metal thioalkoxides having 1 to 6 carbon atoms such assodium thiomethoxide and the like; carbonates such as sodium carbonate,potassium carbonate, cesium carbonate and the like; hydrogencarbonatessuch as sodium hydrogencarbonate, potassium hydrogencarbonate and thelike; acetates such as sodium acetate, potassium acetate and the like;phosphates such as tripotassium phosphate, sodium phosphate and thelike; and monohydrogen phosphates such as potassium monohydrogenphosphate, sodium monohydrogen phosphate and the like.

Examples of the organic base include aliphatic amine as such astrimethylamine, triethylamine, N-methylmorpholine,N,N-diisopropylethylamine, diethylamine, diisopropylamine,cyclohexylamine, ethylenediamine and the like; aromatic amines such aspyridine, picoline, N,N-dimethylaniline and the like; and basic aminoacids such as arginine, lysine, ornithine and the like.

While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (A-c) or a saltthereof. The base can also be used as a solvent.

Examples of the acid which may be added to the reaction system of StepA-2 include mineral acids (specifically hydrofluoric acid, hydrochloricacid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid,sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid,bicarbonic acid and the like); carboxylic acids (i.e., compounds havingone or more carboxy groups; specifically formic acid, acetic acid,trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malic acidand the like); acidic amino acids (specifically aspartic acid, glutamicacid and the like); sulfonic acids (i.e., compounds having one or moresulfo groups; specifically methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid and the like); and Lewis acids (specificallyaluminium chloride, tin chloride, zinc chloride, zinc bromide, titaniumtetrachloride, boron trifluoride-ethyl ether complex and the like).Where necessary, the acid may be used in a mixture of two or more kindsthereof.

While the amount of the acid to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (A-c) or a saltthereof. The acid can also be used as a solvent.

Examples of the salt which may be added to the reaction system of StepA-2 include salts which contain the above-mentioned “acid” as an acidcomponent, in addition to salts exemplified as the above-mentioned“inorganic base”.

While the amount of the salt to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01to 100 mol, per 1 mol of the substrate compound (A-c) or a salt thereof.

As the additive used in the reaction of Step A-2, acids are preferable,acetic acid, p-toluenesulfonic acid (it may be used as a monohydrate)and zinc chloride are more preferable, and acetic acid is particularlypreferable.

While the reaction of Step A-2 may be carried out without a solvent, itis generally carried out in a solvent. The solvent is not particularlylimited as long as it does not inhibit the reaction and can dissolve theraw material compound and additive, and examples thereof include etherssuch as diethyl ether, diisopropyl ether, tert-butyl methyl ether,diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, t-butyl alcohol,3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; esters such as ethyl acetate, isopropyl acetate, n-propylacetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethylformate and the like; nitromethane; water and the like. These solventsmay be used in a mixture in an appropriate ratio.

As the solvent used in the reaction of Step A-2, ethers, alcohols andaromatic hydrocarbons are preferable, tetrahydrofuran, methanol, ethanoland toluene are more preferable, and ethanol is particularly preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of compound (A-c) or a salt thereof,compound (VI-1′) or a salt thereof, or compound (VI′) or a salt thereof,and the like. For example, when an ether (preferably tetrahydrofuran),an alcohol (preferably methanol, ethanol) or an aromatic hydrocarbon(preferably toluene) is used as a solvent, the reaction can be carriedout nearly without a solvent or in a solvent in an amount of 100 partsby weight or less per 1 part by weight of the substrate compound (A-c)or a salt thereof, preferably in a solvent in an amount of 1 to 10 partsby weight per 1 part by weight of the substrate compound (A-c) or a saltthereof.

The temperature in the reaction of Step A-2 is generally 0 to 180° C.,preferably 20 to 120° C. The reaction time is generally 0.1 to 24 hr,preferably 0.5 to 12 hr.

Since water is genereated with the process of the reaction of Step A-2,dehydration may be carried out by adding molecular sieve to the reactionsolution or using Dean-Stark trap, and the like during the reaction.

The compound (I) or a salt thereof in the reaction of Step A-2 may beisolated and purified according to a means known per se (concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like).

[Step A-3]

Step A-3 is a step of producing compound (II) or a salt thereof bysubjecting compound (I) or a salt thereof to an asymmetric reductionreaction.

The “asymmetric reduction reaction” is preferably carried out bysubjecting compound (I) or a salt thereof to a hydrogenation reaction inthe presence of an organic metal complex.

Examples of the “organic metal complex” include typical metal complexessuch as boron complexes, aluminium complexes, gallium complexes and thelike, in addition to a “transition metal complex (an organic transitionmetal complex)”.

The “organic metal complex” is preferably a “transition metal complex(an organic transition metal complex)”.

Examples of the “transition metal complex” include compounds prepared bycoordinating a “ligand” (preferably an optically active “ligand”) to a“transition metal” which have the ability to catalyze an asymmetrichydrogenation reaction. Examples of the “ligand” include monophosphineligands, diphosphine ligands, amine ligands, diamine ligands, phosphineamine ligands and the like, and include specific examples describedherein and optical isomers thereof. The valence of the “transitionmetal” is, for example, 0 to 6, preferably 0 to 4, particularlypreferably 0 to 3.

Preferable examples of the “transition metal complex” include rhodiumcomplexes, ruthenium complexes, iridium complexes, palladium complexes,nickel complexes, copper complexes, osmium complexes, platinumcomplexes, iron complexes, gold complexes, silver complexes, zinccomplexes, titanium complexes, cobalt complexes, zirconium complexes,samarium complexes and the like; more preferred are rhodium complexes,ruthenium complexes, iridium complexes, palladium complexes, nickelcomplexes and copper complexes; further more preferred are rhodiumcomplexes, ruthenium complexes, palladium complexes and iridiumcomplexes; still more preferred are rhodium complexes and iridiumcomplexes; and particularly preferred are iridium complexes.

Among the “transition metal complexes”, specific examples of the rhodiumcomplexes, ruthenium complexes, iridium complexes, palladium complexes,nickel complexes and copper complexes are shown below, wherein, in thetransition metal complexes, L is a diphosphine ligand, a PN ligand, ortwo phosphine ligands (the two monophosphine ligand, each monophosphineligand is the same or different), Ar is benzene optionally havingsubstituent(s) (the substituent is preferably a C₁₋₆ alkyl group), Cp*is pentamethylcyclopentadienyl, Cp is cyclopentadienyl, cod is1,5-cyclooctadiene, Tf is trifluoromethanesulfonyl, nbd isnorbornadiene, Ph is phenyl, Ac is acetyl, Et is ethyl, dmf isN,N-dimethylformamide, 2-methylallyl is η³-2-methylallyl, en isethylenediamine, dpen is 1,2-diphenylethylenediamine, daipen is1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine, and n is an integer of1 or more. 1,2-Diphenylethylenediamine and1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine may be (R)-form,(S)-form and a mixture of (R)-form and (S)-form (the ratio is notlimited), preferably an optically active form.

rhodium complexes: [RhCl(L)]₂, [RhBr(L)]₂, [RhI(L)]₂, [RhCp*(L)]₂, [Rh(cod) (L)]OTf, [Rh (cod) (L)]BF₄, [Rh (cod) (L)]ClO₄, [Rh(cod) (L)]PF₆,[Rh(cod) (L)]SbF₆, [Rh(cod) (L)]BPh₄, [Rh (cod) (L)]B{3, 5-(CF₃)₂C₆H₃}₄,[Rh (nbd) (L)]OTf, [Rh (nbd) (L)]BF₄, [Rh (nbd) (L)]ClO₄, [Rh (nbd)(L)]PF₆, [Rh (nbd) (L)]SbF₆, [Rh (nbd) (L)]BPh₄, [Rh (nbd) (L)]B{3,5-(CF₃)₂C₆H₃}₄, [Rh(L) (CH₃OH)₂]OTf, [Rh(L) (CH₃OH)₂]BF₄, [Rh(L)(CH₃OH)₂]ClO₄, [Rh(L) (CH₃OH)₂]PF₆, [Rh(L) (CH₃OH)₂]BPh₄;

ruthenium complexes: [RuCl₂(L)]n, [RuBr₂(L)]_(n), [RuI₂(L)]_(n),[Ru(OAc)₂(L)], [Ru(OCOCF₃)₂(L)], (NH₂Me₂) [{RuCl(L)}₂ (μ-Cl)₃], (NH₂Et₂)[{RuCl(L)}₂ (μ-Cl)₃], (NH₂Me₂) [{RuBr(L)}₂ (μ-Br)₃], (NH₂Et₂)[{RuBr(L)}₂ (μ-Br)₃], (NH₂Me₂) [{RuI(L)}₂ (μ-I)₃], (NH₂Et₂) [{RuI(L)}₂(μ-I)₃], [Ru₂Cl₄ (L)₂ (NEt₃)], [RuCl₂ (L) (dmf)_(n)],[Ru(2-methylallyl)₂(L)], [RuCl(Ar)(L)]Cl, [RuCl(Ar)(L)]Br, [RuCl(Ar)(L)]I, [RuCl(Ar) (L)]OTf, [RuCl(Ar) (L)]ClO₄, [RuCl(Ar) (L)]PF₆,[RuCl(Ar) (L)]BF₄, [RuCl(Ar) (L)]BPh₄, [RuBr(Ar) (L)]Cl, [RuBr(Ar)(L)]Br, [RuBr(Ar) (L)]I, [RuI(Ar) (L)]Cl, [RuI(Ar) (L)]Br, [RuI(Ar)(L)]I, [Ru(L)](OTf)₂, [Ru(L)](BF₄)₂, [Ru(L)](ClO₄)₂, [Ru(L)](PF₆)₂,[Ru(L)](BPh₄)₂, [RuH(L)₂]Cl, [RuH(L)₂]OTf, [RuH(L)₂]BF₄, [RuH(L)₂]ClO₄,[RuH(L)₂]PF₆, [RuH(L)₂]BPh₄, [RuH(CH₃CN) (L)]Cl, [RuH(CH₃CN) (L)]OTf,[RuH(CH₃CN) (L)]BF₄, [RuH(CH₃CN) (L)]ClO₄, [RuH(CH₃CN) (L)]PF₆,[RuH(CH₃CN) (L)]BPh₄, [RuCl(L)]OTf, [RuCl(L)]BF₄, [RuCl(L)]ClO₄,[RuCl(L)]PF₆, [RuCl(L)]BPh₄, [RuBr(L)]OTf, [RuBr(L)]BF₄, [RuBr(L)]ClO₄,[RuBr(L)]PF₆, [RuBr(L)]BPh₄, [RuI(L)]OTf, [RuI(L)]BF₄, [RuI(L)]ClO₄,[RuI(L)]PF₆, [RuI(L)]BPh₄, [RuCl₂(L) (en)], [RuCl₂(L) (dpen)], [RuCl₂(L) (daipen)], [RuH (η¹-BH₄) (L) (en)], [RuH (ri-BH₄) (L) (daipen)],[RuH(η¹-BH₄) (L) (dpen)](Examples of the diamine ligands correspondingto en, dpen and daipen, which are the diamine ligands in the[RuCl₂(L)(en)], [RuCl₂ (L) (dpen)] and [RuCl₂(L)(daipen)], include1,2-cyclohexanediamine, 1,2-cycloheptanediamine,2,3-dimethylbutanediamine, 1-methyl-2,2-diphenyl-1,2-ethylenediamine,1-isobutyl-2,2-diphenyl-1,2-ethylenediamine,1-isopropyl-2,2-diphenyl-1,2-ethylenediamine,1,1-di(4-anisyl)-2-methyl-1,2-ethylenediamine,1,1-di(4-anisyl)-2-isobutyl-1,2-ethylenediamine,1,1-di(4-anisyl)-2-benzyl-1,2-ethylenediamine,1-methyl-2,2-dinaphthyl-1,2-ethylenediamine,1-isobutyl-2,2-dinaphthyl-1,2-ethylenediamine,1-isopropyl-2,2-dinaphthyl-1,2-ethylenediamine, propanediamine,butanediamine, phenylenediamine and the like, in addition to en, dpenand daipen);

iridium complexes: [IrCl(L)]₂, [IrBr(L)]₂, [IrI(L)]₂, [IrCp*(L)]₂, [Ir(cod) (L)]OTf, [Ir (cod) (L)]BF₄, [Ir (cod) (L)]ClO₄, [Ir (cod) (L)]PF₆,[Ir (cod) (L)]SbF₆, [Ir (cod) (L)]BPh₄, [Ir (nbd) (L)]B(3,5-(CF₃)₂C₆H₃)₄, [Ir (nbd) (L)]OTf, [Ir (nbd) (L)]BF₄, [Ir (nbd)(L)]ClO₄, [Ir (nbd) (L)]PF₆, [Ir (nbd) (L)]SbF₆, [Ir (nbd) (L)]BPh₄, [Ir(nbd) (L)]B(3, 5-(CF₃)₂C₆H₃)₄, [Ir(n-allyl)(L)((C,O)-substituted-benzoate)];

palladium complexes: [PdCl₂(L)], [PdBr₂(L)], [PdI₂(L)], [Pd(n-allyl)(L)]Cl, [Pd(n-allyl) (L)]OTf, [Pd(n-allyl) (L)]BF₄, [Pd(n-allyl)(L)]ClO₄, [Pd(n-allyl) (L)]PF₆, [Pd(n-allyl) (L)]BPh₄, [Pd(L)](OTf)₂,[Pd(L)](BF₄)₂, [Pd(L)](ClO₄)₂, [Pd(L)](PF₆)₂, [Pd(L)](BPh₄)₂, [Pd(L)₂],[Pd(L)₂](OAc)₂, [Pd(L) (H₂O)₂](OTf)₂, [Pd(L) (H₂O)₂](BF₄)₂, [Pd(L)(H₂O)₂](ClO₄)₂, [Pd(L) (H₂O)₂](PF₆)₂, [Pd(L) (H₂O)₂](BPh₄)₂,[{Pd(L)}2(μ-OH)₂](OTf)₂, [{Pd(L)}₂(μ-OH)₂](BF₄)₂,[{Pd(L)}₂(μ-OH)₂](ClO₄)₂, [{Pd(L)}₂(μ-OH)₂](PF₆)₂, [{Pd(L)}₂(μ-OH)₂](BPh₄)₂;

nickel complexes: [NiCl₂(L)], [NiBr₂(L)], [NiI₂(L)], [Ni (n-allyl)(L)]Cl, [Ni (cod) (L)], [Ni (nbd) (L)];

copper complexes: [CuCl(L)], [CuBr(L)], [CuI(L)], [CuH(L)], [Cu(η¹-BH₄)(L)], [Cu(Cp) (L)], [Cu(Cp*) (L)], [Cu(L) (CH₃CN)₂]OTf, [Cu(L)(CH₃CN)₂]BF₄, [Cu(L) (CH₃CN)₂]ClO₄, [Cu(L) (CH₃CN)₂]PF₆, [Cu(L)(CH₃CN)₂]BPh₄

Examples of the above-mentioned diphosphine ligand represented by Linclude 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (hereinafter to bereferred to as BINAP); BINAP derivatives having substituent(s) such as aC₁₋₆ alkyl group, a C₆₋₁₄ aryl group and the like on the naphthylring(s) of BINAP, for example,2,2′-bis(diphenylphosphino)-6,6′-dimethyl-1,1′-binaphthyl; BINAPderivatives wherein the naphthyl ring(s) of BINAP is/are partiallyhydrogenated, for example,2,2′-bis(diphenylphosphino)-5,6,7,8,5′,6′,7′,8′-octahydro-1,1′-binaphthyl(H8BINAP); BINAP derivatives having 1 to 5 substituents such as a C₁₋₆alkyl group, a halogen atom, a mono- or di-C₁₋₆ alkylamino group, a C₁₋₆alkoxy group, a pyrrolidinyl group and the like on the benzene ring(s)bonded to the phosphorus atom of BINAP, for example,2,2′-bis[bis(4-chlorophenyl)phosphino)-1,1′-binaphthyl,2,2′-bis(di-p-tolylphosphino]-1,1′-binaphthyl (tol-BINAP),2,2′-bis[bis(3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl (xyl-BINAP),2,2′-bis[bis(3,5-diethylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(3,5-diisopropylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(3,5-di-tert-butylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(4-dimethylaminophenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(4-dimethylamino-3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(4-dimethylamino-3,5-diethylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(4-dimethylamino-3,5-diisopropylphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(4-diethylaminophenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis[4-(pyrrolidin-1-yl)phenyl]phosphino]-1,1′-binaphthyl,2,2′-bis(di-p-methoxyphenylphosphino)-1,1′-binaphthyl,2,2′-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl,2,2′-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl(DTBM-BINAP);2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl(BICHEP),2,2′-bis(diphenylphosphino)-6,6′-dimethoxybiphenyl (MeO-BIPHEP),2,3-bis(diphenylphosphino)butane (CHIRAPHOS),1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS),1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane (DIPAMP),1,2-bis(diphenylphosphino)propane (PROPHOS),2,4-bis(diphenylphosphino)pentane (SKEWPHOS), SKEWPHOS derivative having1 to 5 substituents such as a C₁₋₆ alkyl group and the like on thebenzene ring(s) bonded to the phosphorus atom of SKEWPHOS,1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethylenediamine (BPPFA),1-substituted-3,4-bis(diphenylphosphino)pyrrolidine (DEGPHOS),2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane(DIOP), substituted-1,2-bisphosphoranobenzene (DuPHOS),substituted-1,2-bisphosphoranoethane (BPE),5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS),N,N′-bis(diphenylphosphino)-N,N′-bis(1-phenylethyl)ethylenediamine(PNNP), 2,2′-diphenylphosphino-1,1′-bicyclopentyl (BICP),4,12-bis(diphenylphosphino)-[2,2]-paracyclophane (PhanePHOS),N-substituted-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine(BoPhoz),1-[2-(disubstituted-phosphino)ferrocenyl]ethyl-disubstituted-phosphine(Josiphos),1-[2-(2′-disubstituted-phosphinophenyl)ferrocenyl]ethyl-disubstituted-phosphine(Walphos),2,2′-bis(α-N,N-dimethylaminophenylmethyl)-1,1′-bis(disubstituted-phosphino)ferrocene(Mandyphos),disubstituted-phosphino-2-[α-(N,N-dimethylamino)-α-disubstituted-phosphinophenyl-methyl]ferrocene(Taniaphos), 1,1-bis(disubstituted-phosphotano)ferrocene (FerroTANE),7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-4,4′-dimethyl-8,8′-bi(2H-1,4-benzoxazine)(Solphos),substituted-1,1′-bisphosphoranoferrocene (Ferrocelane) and the like.

The above-mentioned diphosphine ligand is preferably an optically activeform.

Examples of the above-mentioned two phosphine ligands represented by L(the two monophosphine ligand, each monophosphine ligand is the same ordifferent) include a compound represented by the formula (IX):

whereinA is an optically active skeleton; andR^(8a) and R^(8b) are each independently an optionally substituted C₁₋₆alkyl group, or an optionally substituted C₆₋₁₄ aryl group; a compoundrepresented by the formula (X):

whereinA¹ and A² are each independently an optically active carbon skeleton;R⁹ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₆₋₁₄ aryl group, an optionally substituted aminogroup, an optionally substituted hydroxy group, ferrocenyl orferrocenylmethyl; andA¹ and A² in combination optionally form a 4- to 8-membered ringtogether with the adjacent atom;a compound represented by the formula (XI):

whereinR¹⁰ and R¹¹ are each independently an optionally substituted C₁₋₆ alkylgroup, or an optionally substituted C₆₋₁₄ aryl group;R¹² is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₆₋₁₄ aryl group, an optionally substitutedhydroxy group, or optionally substituted ferrocenyl; andR¹⁰ and R¹¹ in combination optionally form a 4- to 8-membered ringtogether with the adjacent atoms; anda compound represented by the formula (XII):

whereinR¹³ and R¹⁴ are each independently a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, or an optionally substituted C₆₋₁₄ arylgroup;R¹⁵ and R¹⁶ are each independently an optionally substituted C₁₋₆ alkylgroup, or an optionally substituted C₆₋₁₄ aryl group;R¹³ and R¹⁴ in combination optionally form a 4- to 8-membered ringtogether with the adjacent atoms; andR¹⁵ and R¹⁶ in combination optionally form a 4- to 8-membered ringtogether with the adjacent atom.

Examples of the above-mentioned optically active skeleton represented byA include skeletons represented by the following formulas.

whereinthe carbon atom marked with * is an asymmetric carbon atom; and the bondaxis marked with * is an asymmetric axis.

Examples of the “substituent” of the “optionally substituted C₁₋₆ alkylgroup” represented by R^(8a) or R^(8b) include the above-mentioned“substituents”. The number of the substituents in the “optionallysubstituted C₁₋₆ alkyl group” represented by R^(8a) or R^(8b) is, forexample, 1 to 5, preferably 1 to 3, at substitutable position(s). Whenthe number of the substituents is two or more, the respectivesubstituents may be the same or different.

The substituents in the “optionally substituted C₆₋₁₄ aryl group”represented by R^(8a) or R^(8b) and a number thereof are similar tothose exemplified in the above-mentioned “optionally substituted C₆₋₁₄aryl group” represented by R⁷.

Examples of the optically active skeleton represented by A¹ or A²include skeletons represented by the following formulas.

wherein each symbol is as defined above.

When A¹ and A² in combination form a 4- to 8-membered ring together withthe adjacent atom, examples of the compound (X) include

a compound represented by the formula (X-a):

whereinR^(Xa) and R^(Xb) are each independently a C₁₋₆ alkyl group, a C₃₋₁₀cycloalkyl group, an optionally substituted C₆₋₁₄ aryl group, a C₇₋₁₆aralkyl group, an optionally substituted ferrocenyl, orferrocenylmethyl, andthe other symbols are as defined above;a compound represented by the formula (X-b):

whereinR^(Xc) and R^(Xd) are each independently a hydrogen atom, a C₁₋₆ alkylgroup, a C₃₋₁₀ cycloalkyl group, an optionally substituted C₆₋₁₄ arylgroup, or a C₇₋₁₆ aralkyl group;R^(Xe) and R^(Xf) are each independently a hydrogen atom, or anoptionally substituted hydroxy group, andthe other symbols are as defined above;a compound represented by the formula (X-c):

wherein each symbol is as defined above;a compound represented by the formula (X-d):

whereinR^(Xg) and R^(Xh) are each independently a hydrogen atom, a C₁₋₆ alkylgroup, a C₃₋₁₀ cycloalkyl group, an optionally substituted C₆₋₁₄ arylgroup, or a C₇₋₁₆ aralkyl group, andthe other symbols are as defined above; anda compound represented by the formula (X-e):

whereinR^(Xi) and R^(Xj) are each independently a hydrogen atom, a C₁₋₆ alkylgroup, a C₃₋₁₀ cycloalkyl group, an optionally substituted C₆₋₁₄ arylgroup, or a C₇₋₁₆ aralkyl group, andthe other symbols are as defined above.

Preferable examples of the substituent of the “optionally substitutedC₆₋₁₄ aryl group” represented by R^(Xa), R^(Xb), R^(Xc), R^(Xd), R^(Xg),R^(Xh), R^(Xi) or R^(Xj) include a halogen atom, a C₁₋₆ alkyl group anda C₁₋₆ alkoxy group.

Preferable examples of the substituent of the “optionally substitutedferrocenyl” represented by R^(Xa) or R^(Xb) include a C₁₋₆ alkyl group.

Preferable examples of the substituent of the “optionally substitutedhydroxy group” represented by Re or R^(X)r include a C₁₋₆ alkyl groupand a C₇₋₁₆ aralkyl group.

R⁹ is preferably a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₆₋₁₄ aryl group, an optionallysubstituted amino group, or an optionally substituted hydroxy group.

Preferable examples of the substituent of the “optionally substitutedC₁₋₆ alkyl group” include a C₆₋₁₄ aryl group.

Preferable examples of the substituent of the “optionally substitutedC₆₋₁₄ aryl group” include a halogen atom, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group.

Preferable examples of the substituent of the “optionally substitutedamino group” include

(1) a C₁₋₆ alkyl group optionally substituted by C₆₋₁₄ aryl group(s)optionally having 1 to 3 of C₁₋₆ alkoxy groups or C₁₋₆ alkyl groups and(2) a C₆₋₁₄ aryl group optionally having 1 to 3 of C₁₋₆ alkoxy groups orC₁₋₆ alkyl groups.

Preferable examples of the substituent of the “optionally substitutedhydroxy group” include

(1) a C₁₋₆ alkyl group optionally substituted by C₆₋₁₄ aryl group(s)optionally having 1 to 3 of C₁₋₆ alkoxy groups or C₁₋₆ alkyl groups, and(2) a C₆₋₁₄ aryl group optionally having 1 to 3 of C₁₋₆ alkoxy groups orC₁₋₆ alkyl groups.

Examples of the cyclic structural moiety in compound (XI) when R¹⁰ andR¹¹ in combination form a 4- to 8-membered ring together with theadjacent atoms, and the cyclic structural moiety in compound (XII) whenR¹³ and R¹⁴ in combination form a 4- to 8-membered ring together withthe adjacent atoms, include a cyclic structural moiety represented bythe formula (XI-1), (XI-2) or (XI-3):

wherein each symbol is as defined above;a cyclic structural moiety represented by the formula (XI-a):

whereinR^(XIa1), R^(XIa2), R^(XIa3) and R^(XIa4) are each independently anoptionally substituted C₆₋₁₄ aryl group, andthe other symbols are as defined above;a cyclic structural moiety represented by the formula (XI-b):

whereinR^(XIb1), R^(XIb2), R^(XIb3), R^(XIb4), R^(XIb5), R^(XIb6), R^(XIb7),R^(XIb8), R^(XIb9), and R^(XIb10) are each independently a hydrogenatom, a halogen atom, a C₁₋₆ alkyl group, an optionally substitutedC₆₋₁₄ aryl group, or a C₁₋₆ alkoxy group;R^(XIb1) and R^(XIb3) in combination optionally form a 4- to 8-memberedring together with the adjacent atoms;R^(XIb2) and R^(XIb4) in combination optionally form a 4- to 8-memberedring together with the adjacent atoms;R^(XIb5) and R^(XIb7) in combination optionally form a 4- to 8-memberedring together with the adjacent atoms;R^(XIb6) and R^(XIb8) in combination optionally form a 4- to 8-memberedring together with the adjacent atoms; and the other symbols are asdefined above;a cyclic structural moiety represented by the formula (XI-c):

whereinR^(XIc1) and R^(XIc2) are each independently a hydrogen atom, a halogenatom, a C₁₋₆ alkyl group, an optionally substituted C₆₋₁₄ aryl group, ora C₁₋₆ alkoxy group; andthe other symbols are as defined above;a cyclic structural moiety represented by the formula (XI-d):

wherein R^(XId1), R^(XId2), R^(XId3), R^(XId4), R^(XId5) and R^(XId6)are each independently a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, an optionally substituted C₆₋₁₄ aryl group, or a C₁₋₆ alkoxygroup; andthe other symbols are as defined above;a cyclic structural moiety represented by the formula (XI-e):

whereinR^(XIe1), R^(XIe2), R^(XIe3) and R^(XIe4) are each independently ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, an optionallysubstituted C₆₋₁₄ aryl group, or a C₁₋₆ alkoxy group;R^(XIe5) and R^(XIe6) are each independently a hydrogen atom, a C₁₋₆alkyl group, or an optionally substituted C₆₋₁₄ aryl group; and theother symbols are as defined above; anda cyclic structural moiety represented by the formula (XI-f):

whereinR^(XIf1), and R^(XIf2) are each independently a hydrogen atom, a halogenatom, or a C₁₋₆ alkyl group; and the other symbols are as defined above.

Preferable examples of the substituent of the “optionally substitutedC₆₋₁₄ aryl group” represented by R^(XIa1), R^(XIa2), R^(XIa3), R^(XIa4),R^(XIb1), R^(XIb2), R^(XIb3), R^(XIb4), R^(XIb5), R^(XIb6), R^(XIb7),R^(XIb8), R^(XIb9), R^(XIb10), R^(XIc1), R^(XIc2), R^(XId1), R^(XId2),R^(XId3), R^(XId4), R^(XId5), R^(XId6), R^(XIe1), R^(XIe2), R^(XIe3),R^(XIe4), R^(XIe5) or R^(XIe6) include a halogen atom, a C₁₋₆ alkylgroup and a C₁₋₆ alkoxy group.

Preferably, R¹⁰ and R¹¹ in combination form a 4- to 8-membered ringtogether with the adjacent atoms, and the cyclic structural moiety ispreferably the structure represented by the formula (XI-1).

Preferably, R¹³ and R¹⁴ in combination form a 4- to 8-membered ringtogether with the adjacent atoms, and the cyclic structural moiety ispreferably the structure represented by the formula (XI-1).

R¹² is preferably an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₆₋₁₄ aryl group, or an optionally substitutedhydroxy group.

Preferable examples of the substituent of the “optionally substitutedC₁₋₆ alkyl group” include a C₆₋₁₄ aryl group.

Preferable examples of the substituent of the “optionally substitutedC₆₋₁₄ aryl group” include a halogen atom, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group.

Preferable examples of the substituent of the “optionally substitutedhydroxy group” include

(1) a C₁₋₆ alkyl group optionally substituted by

(a) a C₆₋₁₄ aryl group optionally having 1 to 3 of C₁₋₆ alkoxy groups orC₁₋₆ alkyl groups, or

(b) an amino group optionally having 1 to 2 C₁₋₆ alkyl groups,

(2) a C₃₋₁₀ cycloalkyl group optionally having 1 to 3 of C₁₋₆ alkoxygroups or C₁₋₆ alkyl groups, and,(3) a C₆₋₁₄ aryl group optionally having 1 to 3 of C₁₋₆ alkoxy groups orC₁₋₆ alkyl groups.

R¹⁵ and R¹⁶ are preferably each independently an optionally substitutedC₁₋₆ alkyl group.

The number of the substituents in the “optionally substituted C₁₋₆ alkylgroup” is, for example, 1 to 5, preferably 1 to 3, at substitutableposition(s). When the number of the substituents is two or more, therespective substituents may be the same or different.

Preferable examples of the substituent of the “optionally substitutedC₁₋₆ alkyl group” include a C₆₋₁₄ aryl group optionally having 1 to 3 ofC₁₋₆ alkoxy groups or C₁₋₆ alkyl groups.

Examples of the cyclic structural moiety in compound (XII) when R¹⁵ andR¹⁶ in combination form a 4- to 8-membered ring together with theadjacent atom include

a cyclic structural moiety represented by the formula (XI-g):

wherein

R^(XIg1) and R^(XIg2) are each independently a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₃₋₁₀cycloalkyl group, or an optionally substituted C₆₋₁₄ aryl group;

Y is —(CH₂)₂—, —(CH₂)₃— or —CH₂—O—CH₂—; and the other symbols are asdefined above; anda cyclic structural moiety represented by the formula (XI-h):

whereinR^(XIh1) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, anoptionally substituted C₆₋₁₄ aryl group, or a C₁₋₆ alkoxy group;R^(XIh2) is a hydrogen atom, a C₁₋₆ alkyl group, or an optionallysubstituted C₆₋₁₄ aryl group; andthe other symbols are as defined above.

Examples of the “substituent” of the “optionally substituted C₁₋₆ alkylgroup” represented by R^(XIg1) or R^(XIg2) include the above-mentioned“substituents”. The number of the substituents is, for example, 1 to 5,preferably 1 to 3, at substitutable position(s). When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Preferable examples of the “substituent” of the “optionally substitutedC₁₋₆ alkyl group” represented by R^(XIg1) or R^(XIg2) include a C₁₋₆alkyl group, a C₃₋₁₀ cycloalkyl group and a C₆₋₁₄ aryl group.

The “substituent” of the “optionally substituted C₃₋₁₀ cycloalkyl group”represented by R^(XIg1) or R^(XIg2) and a number thereof are similar tothose exemplified in the above-mentioned “optionally substituted C₁₋₆alkyl group” represented by R^(XIg1) or R^(XIg2). Preferred are a C₁₋₆alkyl group, a C₃₋₁₀ cycloalkyl group and a C₆₋₁₄ aryl group.

The “substituent” of the “optionally substituted C₆₋₁₄ aryl group”represented by R^(XIg1) or R^(XIg2) and a number thereof are similar tothose exemplified in the above-mentioned “optionally substituted C₁₋₆alkyl group” represented by R^(XIg1) or R^(XIg2). Preferred are ahalogen atom, a C₁₋₆ alkyl group, a C₃₋₁₀ cycloalkyl group and a C₆₋₁₄aryl group.

Preferable examples of the “substituent” of the “optionally substitutedC₆₋₁₄ aryl group” represented by R^(XIh1) include a halogen atom, a C₁₋₆alkyl group, a C₃₋₁₀ cycloalkyl group and a C₆₋₁₄ aryl group.

R^(XIh1) is preferably a hydrogen atom or a halogen atom.

Preferable examples of the “substituent” of the “optionally substitutedC₆₋₁₄ aryl group” represented by R^(XIh2) include a halogen atom, a C₁₋₆alkyl group, a C₃₋₁₀ cycloalkyl group and a C₆₋₁₄ aryl group.

R^(XIh2) is preferably a hydrogen atom or a C₁₋₆ alkyl group.

Specific examples of the above-mentioned two phosphine ligands (the twomonophosphine ligand, each monophosphine ligand is the same ordifferent) represented by L include

-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine    (MonoPhos),-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)benzyl(methyl)amine,-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-(1-phenylethyl)amine,-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)bis(1-phenylethyl)amine,-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-2,5-diphenylpyrrolidine,-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)morpholine    (Morfphos),-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)piperidine    (PipPhos),-   2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthoyl (MOP),-   1-(2-diphenylphosphino-1-naphthyl)isoquinoline (QUINAP),-   N-dimethyl-[1,1-spirobiindane-7,7′-diyl]phosphoramidite (SIPHOS),-   N-di[(1-phenylethyl]-[1,1-spirobiindane-7,7-diyl]phosphoramidite    (SIPHOS-PE),-   (3aR,8aR)-(−)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl)dimethylamine,-   (3aS,8aS)-(−)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl)dimethylamine,-   5-[(3aR,8aR)-tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl]-5H-dibenzo[b,f]azepine,-   5-[(3aS,8aS)-tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl]-5H-dibenzo[b,f]azepine,-   N-[(2S,5S)-4,4-diphenyl-3-oxa-1-aza-2-phosphabicyclo[3.3.0]octan-2-yl]dibenzo[b,f]azepine    and the like.

The two phosphine ligands (the two monophosphine ligand, eachmonophosphine ligand is the same or different) represented by L ispreferably an optically active form.

Specific examples of the PN ligand represented by L include

-   2-[(6-(diphenylphosphino)spiro[4.4]nona-1,6-dien-1-yl]-4,5-dihydro-4-benzyloxazole    (Bn-SpinPHOX),-   2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole    (iPr-Phox)    and the like.

The PN ligand represented by L is preferably an optically active form.

The “ligand” used for the “transition metal complex” is preferably anoptically active ligand.

The “transition metal complex” can be prepared from a “ligand” and theother complex as a transition metal source according to a means knownper se (preparation of rhodium complexes; Journal of the AmericanChemical Society (J. Am. Chem. Soc.), vol. 94, page 6429, 1972, OrganicSynthesis (Org. Synth.), vol. 67, page 33, 1989: preparation ofruthenium complexes; Journal of Organic Chemistry (J. Org. Chem.), vol.57, page 4053, 1992, Tetrahedron Asymmetry (Tetrahedron Asym.), vol. 2,page 43, 1991, Journal of Organic Chemistry (J. Org. Chem.), vol. 59,page 3064, 1994, Angewandte Chemie International Edition (Angew. Chem.Int. Ed.), vol. 37, page 1703, 1998: preparation of iridium complexes;Journal of Organometallic Chemistry (J. Organomet. Chem.), vol. 428,page 213, 1992: preparation of palladium complexes; Organometallics,vol. 12, page 4188, 1993, Journal of the American Chemical Society (J.Am. Chem. Soc.), vol. 121, page 5450, 1999: preparation of nickelcomplexes; “5th Ed., Jikken Kagaku Koza” edited by Japan ChemicalSociety (Maruzen), vol. 21, organic transition metal compound,Supermolecular Complex, pages 293-294 (2004): preparation of coppercomplexes; “5th Ed., Jikken Kagaku Koza” edited by Japan ChemicalSociety (Maruzen), vol. 21, organic transition metal compound,Supermolecular Complex, page 357 (2004), Journal of Organic Chemistry(J. Org. Chem.), vol. 63, page 6090, 1998), and can be isolated orpurified according to a means known per se (e.g., concentration, solventextraction, fractional distillation, crystallization, recrystallization,chromatography).

Among the “diphosphine ligand” represented by L, SKEWPHOS derivativehaving 1 to 5 substituents such as a C₁₋₆ alkyl group and the like onthe one benzene ring bonded to the phosphorus atom of SKEWPHOS can besynthesized according to the method described in the Patent Document WO2013/146987.

The two phosphine ligands (the two monophosphine ligand, eachmonophosphine ligand is the same or different) represented by L can beprepared according to a means known per se (Wiley, Phosphorus Ligands inAsymmetric Catalysis, vol. 1, pages 5-69, (2008)), and can be isolatedor purified according to a means known per se (e.g., concentration,solvent extraction, fractional distillation, crystallization,recrystallization, chromatography).

The “transition metal complex” can also be prepared by adding a “ligand”and the other complex as a transition metal source to a reaction system.The “transition metal complex” may be directly added to a reactioncontainer, or may be prepared by adding a “transition metal source”mentioned above and a “ligand” to a reaction container. When the“transition metal complex” is prepared by adding a “transition metalsource” and a “ligand” to a container, the “ligand” is used in an amountof 1- to 100-fold by mole, preferably 1 to 5-fold by mole, further morepreferably 1.01 to 2.02-fold by mole, relative to the theoretical molerequired to prepare the “transition metal complex”.

While the amount of the “transition metal complex” to be used variesdepending on the reaction container, the style of the reaction, and thelike, it is, for example, about 1.0-about 0.00001 mol, per 1 mol of thesubstrate compound (I) or a salt thereof.

In the “hydrogenation reaction” of Step A-3, hydrogen gas, metalhydride, isopropyl alcohol, formic acid, benzthiazoline, Hantzsch esterand the like can be used as a hydrogen donor. Among them, hydrogen gasis preferably used.

When hydrogen gas is used, the hydrogenation reaction can be carried outby batch process or continuous process. When the hydrogenation reactionis carried out in the presence of hydrogen gas, the hydrogen pressureis, for example, 0.001 to 200 atm, preferably 0.1 to 15 atm.

In the “hydrogenation reaction” of Step A-3, an additive such as a base,an acid, a salt and the like may be added, if necessary. The additivemay be used in a mixture of two or more kinds thereof. The additive maybe added to a reaction container before or during the “hydrogenationreaction”.

Examples of the base which may be added to the “hydrogenation reaction”system of Step A-3 include inorganic bases and organic bases.

Examples of the inorganic base include alkali metal hydroxides such aslithium hydroxide, potassium hydroxide, sodium hydroxide, cesiumhydroxide and the like; alkali metal alkoxides having 1 to 6 carbonatoms such as lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide, lithiumpropoxide, sodium propoxide, potassium propoxide, lithium isopropoxide,sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide andthe like; alkali metal thioalkoxides having 1 to 6 carbon atoms such assodium thiomethoxide and the like; carbonates such as sodium carbonate,potassium carbonate, cesium carbonate and the like; hydrogencarbonatessuch as sodium hydrogencarbonate, potassium hydrogencarbonate and thelike; acetates such as sodium acetate, potassium acetate and the like;phosphates such as tripotassium phosphate, sodium phosphate and thelike; and monohydrogen phosphates such as potassium monohydrogenphosphate, sodium monohydrogen phosphate and the like.

Examples of the organic base include aliphatic amine as such astrimethylamine, triethylamine, N-methylmorpholine,N,N-diisopropylethylamine, diethylamine, diisopropylamine,cyclohexylamine, ethylenediamine and the like; aromatic amines such aspyridine, picoline, N,N-dimethylaniline and the like; and basic aminoacids such as arginine, lysine, ornithine and the like.

While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (I) or a salt thereof.The base can also be used as a solvent.

Examples of the acid which may be added to the “hydrogenation reaction”system of Step A-3 include mineral acids (specifically hydrofluoricacid, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid,carbonic acid, bicarbonic acid and the like); carboxylic acids (i.e.,compounds having one or more carboxy groups; specifically formic acid,acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid and the like); acidic amino acids (specificallyaspartic acid, glutamic acid and the like); and sulfonic acids (i.e.,compounds having one or more sulfo groups; specifically methanesulfonicacid, trifluoromethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid and the like). Wherenecessary, the acid may be used in a mixture of two or more kindsthereof.

While the amount of the acid to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (I) or a salt thereof.The acid can also be used as a solvent.

Examples of the salt which may be added to the “hydrogenation reaction”system of Step A-3 include salts which contain the above-mentioned“acid” as an acid component, in addition to salts exemplified as theabove-mentioned “inorganic base”.

While the amount of the salt to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01to 100 mol, per 1 mol of the substrate compound (I) or a salt thereof.

The “hydrogenation reaction” of Step A-3 is generally carried out in asolvent. The solvent is not particularly limited as long as it does notinhibit the reaction and can dissolve the raw material compound, organicmetal complex and additive, and examples thereof include ethers such asdiethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenylether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-butanol, t-butylalcohol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzylalcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and thelike; aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate compound (I) or a saltthereof, and the like. The reaction can be carried out nearly without asolvent or in a solvent in an amount of 100 parts by weight or less per1 part by weight of the substrate compound (I) or a salt thereof,preferably in a solvent in an amount of about 2-about 100 parts byweight per 1 part by weight of the substrate compound (I) or a saltthereof.

The temperature in the “hydrogenation reaction” of Step A-3 is generally−30 to 160° C., preferably 0 to 120° C., more preferably 10 to 80° C.The reaction time is generally 0.1 to 120 hr, preferably 1 to 72 hr.

Compound (II) or a salt thereof obtained in the “hydrogenation reaction”may be purified according to a means known per se (e.g., fractionalrecrystallization method, chiral column method, diastereomer saltmethod).

Alternatively, Compound (II) or a salt thereof obtained in the“hydrogenation reaction” may be treated according to a means known perse (e.g., concentration, solvent extraction, chromatography) ifnecessary, and then the obtained solution may be directly used in thenext Step A-4, without isolation.

[Step A-4]

Step A-4 is a step of producing compound (III) or a salt thereof bysubjecting compound (II) or a salt thereof to a deprotection reaction.

When PG is a group represented by the formula (VI-1), the deprotectionreaction can be carried out according to a method known per se (e.g.,the method described in Synthetic Communications, vol 10, page 253,1980; Tetrahedron, vol. 50, page 4399, 1994).

When PG is a group represented by the formula (VI), the deprotectionreaction can be carried out according to a method known per se (e.g.,the method described in Protective Group in Organic Synthesis, the 3rdedition, pages 579-583, 1999).

In case of preferable embodiment wherein compound (I) or a salt thereofis compound (VII) or a salt thereof, and compound (II) or a salt thereofis compound (VIII) or a salt thereof, Step A-3 and Step A-4 in theproduction method of compound (III) or a salt thereof are explainedbelow in detail.

The “transition metal complex” used in the “hydrogenation reaction” ofStep A-3 in the preferable embodiment is particularly preferably aniridium complex.

The ligand for the “iridium complex” is preferably a monophosphineligand, more preferably the compound represented by the formula (XI) orthe compound represented by the formula (XII), further more preferablythe compound represented by the formula (XII), particularly preferablythe compound having the cyclic structural moiety represented by theformula (XI-b). Specific examples thereof include,

-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine    (MonoPhos);-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)benzyl(methyl)amine;-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-(1-phenylethyl)amine;-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)bis(1-phenylethyl)amine;-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-2,5-diphenylpyrrolidine;-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)morpholine    (Morfphos); and-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)piperidine    (PipPhos).

Preferred are

-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine    (MonoPhos);-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)morpholine    (Morfphos); and-   (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)piperidine    (PipPhos),    particularly preferred is    (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine    (MonoPhos).

The “iridium complex” is preferably prepared by adding a “ligand” andthe other iridium complex as an iridium metal source to a reactionsystem.

The “other iridium complex as an iridium metal source” is particularlypreferably bis(cyclooctadiene)iridium(I)tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

Preferable examples of the solvent used in the “hydrogenation reaction”include toluene and dichloromethane, and particularly preferred isdichloromethane.

The “deprotection reaction” of Step A-4 in the preferable embodiment canbe carried out according to a method known per se (i.e., the methoddescribed in Synthesis, vol. 4, page 570, 2003; Organic Letters, vol. 1,page 1395, 1999; Tetrahedron, vol. 52, page 10685, 1996; TetrahedronLetters, vol. 32, page 5865, 1991).

The “deprotection reaction” is preferably carried out by reactingcompound (VIII) or a salt thereof with triethylsilane in the presence ofan acid.

Examples of the “acid” include mineral acids (specifically hydrofluoricacid, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid,carbonic acid, bicarbonic acid and the like); carboxylic acids (i.e.,compounds having one or more carboxy groups; specifically formic acid,acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid and the like); acidic amino acids (specificallyaspartic acid, glutamic acid and the like); sulfonic acids (i.e.,compounds having one or more sulfo groups; specifically methanesulfonicacid, trifluoromethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid and the like); and Lewisacids (specifically aluminium chloride, tin chloride, zinc chloride,zinc bromide, titanium tetrachloride, boron trifluoride-ethyl ethercomplex and the like). Where necessary, the acid may be used in amixture of two or more kinds thereof. Preferred are trifluoroacetic acidand Lewis acids, more preferred are Lewis acids, and particularlypreferred is aluminium chloride.

While the amount of the triethylsilane to be used in the “methodreacting with triethylsilane” varies depending on the kind of thesolvent and the other reaction condition, it is generally 0.1 to 30 mol,preferably 1.5 to 10 mol, per 1 mol of the substrate compound (VIII) ora salt thereof.

While the amount of the acid to be used in the “method reacting withtriethylsilane” varies depending on the kind of the solvent and theother reaction condition, it is generally 0.1 to 30 mol, preferably 1.5to 10 mol, per 1 mol of the substrate compound (VIII) or a salt thereof.

While the “method reacting with triethylsilane” may be carried outwithout a solvent, it is generally carried out in a solvent. The solventis not particularly limited as long as it does not inhibit the reactionand can dissolve the raw material compound and additive, and examplesthereof include ethers such as diethyl ether, diisopropyl ether,tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane,methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane,1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole and the like;alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol,2-butanol, t-butyl alcohol, 3-methyl-1-butanol, 2-methyl-1-propanol,1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethyleneglycol and the like; aromatic hydrocarbons such as benzene, toluene,xylene, cumene, chlorobenzene and the like; saturated hydrocarbons suchas hexane, heptane, pentane, cyclohexane, methylcyclohexane, isooctane,petroleum ether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.As the solvent used in the above-mentioned “method reacting withtriethylsilane”, halogenated hydrocarbons and aromatic hydrocarbons arepreferable, toluene, dichloromethane and 1,2-dichloroethane are morepreferable, and 1,2-dichloroethane is particularly preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate compound (VIII) or a saltthereof, and the like. For example, when a halogenated hydrocarbon(preferably 1,2-dichloroethane) is used as a solvent, the reaction canbe carried out nearly without a solvent or in a solvent in an amount of100 parts by weight or less per 1 part by weight of the substratecompound (VIII) or a salt thereof, preferably in a solvent in an amountof 1 to 30 parts by weight per 1 part by weight of the substratecompound (VIII) or a salt thereof.

The temperature in the above-mentioned “method reacting withtriethylsilane” is generally 10 to 180° C., preferably 30 to 120° C. Thereaction time is generally 0.1 to 96 hr, preferably 0.5 to 48 hr.

Compound (III) wherein R² is a chlorine atom and R³ is trifluoromethylor a salt thereof, which is obtained in the above-mentioned “methodreacting with triethylsilane”, may be purified according to a meansknown per se (e.g., fractional recrystallization method, chiral columnmethod, diastereomer salt method).

In order to obtain the above-mentioned compound (III) or a salt thereofwith high optical purity, it is preferably purified by a fractionalrecrystallization method or a diastereomer salt method, preferablycrystallization of the diastereomer salt with optically activedi-p-toluoyl-tartaric acid (preferably di-p-toluoyl-(D)-tartaric acidwhen the above-mentioned compound (III) is (R)-form) or optically activemandelic acid (preferably (S)-mandelic acid when the above-mentionedcompound (III) is (R)-form), particularly preferably crystallization ofthe diastereomer salt with optically active mandelic acid (preferably(S)-mandelic acid when the above-mentioned compound (III) is (R)-form).

The “deprotection reaction” is also preferably carried out by reactingcompound (VIII) or a salt thereof with an oxidizing agent.

Preferable examples of the “oxidizing agent” include N-bromosuccinimideand N-chlorosuccinimide, and particularly preferred isN-bromosuccinimide.

While the amount of the “oxidizing agent” to be used varies depending onthe kinds of the oxidizing agent and solvent and the other reactioncondition, it is generally 0.8 to 30 mol, preferably 0.9 to 2 mol, per 1mol of the substrate compound (VIII) or a salt thereof.

An additive is preferably used in the reaction by the “method reactingwith an oxidizing agent”. As the “additive”, water and an acid arepreferable.

Examples of the “acid” include mineral acids (specifically hydrofluoricacid, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid,carbonic acid, bicarbonic acid and the like); carboxylic acids (i.e.,compounds having one or more carboxy groups; specifically formic acid,acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid and the like); acidic amino acids (specificallyaspartic acid, glutamic acid and the like); and sulfonic acids (i.e.,compounds having one or more sulfo groups; specifically methanesulfonicacid, trifluoromethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid and the like). Wherenecessary, the acid may be used in a mixture of two or more kindsthereof.

As the additive used in the reaction by the “method reacting with anoxidizing agent”, water, acetic acid, citric acid and hydrochloric acidare preferable, and water is particularly preferable.

While the amount of the “additive” to be used varies depending on thekinds of the additive and solvent and the other reaction condition, itis generally 0.8 to 100 mol, preferably 5 to 50 mol, per 1 mol of thesubstrate compound (VIII) or a salt thereof.

While the reaction by the “method reacting with an oxidizing agent” maybe carried out without a solvent, it is generally carried out in asolvent. The solvent is not particularly limited as long as it does notinhibit the reaction and can dissolve the raw material compound andadditive, and examples thereof include ethers such as diethyl ether,diisopropyl ether, tert-butyl methyl ether, diphenyl ether,tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, t-butyl alcohol,3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.As the solvent used in the reaction by the “method reacting with anoxidizing agent”, acetonitrile is preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate compound (VIII) or a saltthereof, and the like. For example, when water is used as an additiveand acetonitrile is used as a solvent, the reaction can be carried outnearly without a solvent or in a solvent in an amount of 100 parts byweight or less per 1 part by weight of the substrate compound (VIII) ora salt thereof, preferably in a solvent in an amount of 1 to 20 parts byweight per 1 part by weight of the substrate compound (VIII) or a saltthereof.

The temperature in the reaction by the “method reacting with anoxidizing agent” is generally −10 to 120° C., preferably 0 to 60° C. Thereaction time is generally 0.1 to 96 hr, preferably 0.5 to 48 hr.

Compound (III) wherein R² is a chlorine atom and R³ is trifluoromethylor a salt thereof, which is obtained by the above-mentioned “methodreacting with an oxidizing agent”, may be purified according to a meansknown per se (e.g., fractional recrystallization method, chiral columnmethod, diastereomer salt method).

In order to obtain compound (III) or a salt thereof with high opticalpurity, it is preferably purified by a fractional recrystallizationmethod or a diastereomer salt method.

While the undesired enantiomer may be removed as a crystal by afractional recrystallization method, compound (III) or a salt thereof ispreferably purified by crystallization of the diastereomer salt withoptically active di-p-toluoyl-tartaric acid (preferablydi-p-toluoyl-(D)-tartaric acid when the above-mentioned compound (III)is (R)-form) or optically active mandelic acid (preferably (S)-mandelicacid when the above-mentioned compound (III) is (R)-form), particularlypreferably crystallization of the diastereomer salt with opticallyactive mandelic acid (preferably (S)-mandelic acid when theabove-mentioned compound (III) is (R)-form).

[Production Method (AX)]

Compound (III) or a salt thereof can also be directly synthesized bysubjecting compound (A-c) or a salt thereof to an asymmetric reductiveamination reaction according to Production Method (AX) shown in thefollowing scheme.

Production Method (AX)

wherein each symbol is as defined above.

The reagent and condition used in Step A-X are explained in detail.

[Step (A-X)]

Step A-X is a step of producing compound (III) or a salt thereof bysubjecting compound (A-c) or a salt thereof to an asymmetric reductiveamination reaction.

The “asymmetric reductive amination reaction” is preferably carried outby reacting compound (A-c) or a salt thereof with an amine source and areducing agent in the presence of an organic metal complex.

As the “reducing agent”, a hydrogen donor is used. As a hydrogen donor,hydrogen gas, a metal hydride, isopropyl alcohol, formic acid,benzthiazoline, Hantzsch ester and the like can be used. Among them,hydrogen gas is preferably used.

When hydrogen gas is used, the reaction can be carried out by batchprocess or continuous process. When the “asymmetric reductive aminationreaction” is carried out in the presence of hydrogen gas, the hydrogenpressure is, for example, 0.001 to 200 atm, preferably 0.1 to 80 atm.

The “amine source” is preferably an ammonium salts. Preferable examplesof the acid to be used for forming an ammonium salt include anoptionally substituted salicylic acid, an optionally substitutednicotinic acid, carbonic acid, formic acid, acetic acid, trifluoroaceticacid and benzoic acid.

Examples of the substituent of the optionally substituted salicylic acidinclude the above-mentioned “substituents”. The number of thesubstituent is, for example, 1 to 4, preferably 1, at substitutableposition(s).

Preferable examples of the optionally substituted salicylic acid includecompounds shown below.

Examples of the substituent of the optionally substituted nicotinic acidinclude the above-mentioned “substituents”. The number of thesubstituent is, for example, 1 to 4, preferably 1, at substitutableposition(s).

Examples of the “organic metal complex” include those similar to the“organic metal complex” used in the above-mentioned “Step (A-3)”.

The “organic metal complex” is preferably a “transition metal complex(an organic transition metal complex)”.

Examples of the “transition metal complex” include compounds prepared bycoordinating a “ligand” (preferably an optically active “ligand”) to a“transition metal” which have the ability to catalyze an asymmetrichydrogenation reaction. Examples of the “ligand” include monophosphineligands, diphosphine ligands, amine ligands, diamine ligands, phosphineamine ligands and the like, and include specific examples describedherein and optical isomers thereof. The valence of the “transitionmetal” is, for example, 0 to 6, preferably 0 to 4, particularlypreferably 0 to 3.

Preferable examples of the “transition metal complex” include rhodiumcomplexes, ruthenium complexes, iridium complexes, palladium complexes,nickel complexes, copper complexes, osmium complexes, platinumcomplexes, iron complexes, gold complexes, silver complexes, zinccomplexes, titanium complexes, cobalt complexes, zirconium complexes,samarium complexes and the like; more preferred are rhodium complexes,ruthenium complexes, iridium complexes, palladium complexes, nickelcomplexes and copper complexes; further more preferred are rhodiumcomplexes, ruthenium complexes, palladium complexes and iridiumcomplexes; still more preferred are rhodium complexes and iridiumcomplexes; and particularly preferred are iridium complexes.

Among the “transition metal complexes”, specific examples of the rhodiumcomplexes, ruthenium complexes, iridium complexes, palladium complexes,nickel complexes and copper complexes include those similar to thespecific examples of the “organic metal complex” used in theabove-mentioned “Step (A-3)”.

The “transition metal complex” can also be prepared by adding a “ligand”and the other complex as a transition metal source to a reaction system.The “transition metal complex” may be directly added to a reactioncontainer, or may be prepared by adding a “transition metal source”mentioned above and a “ligand” to a reaction container. When the“transition metal complex” is prepared by adding a “transition metalsource” and a “ligand” to a reaction container, the “ligand” is used inan amount of 1- to 100-fold by mole, preferably 1 to 5-fold by mole,further more preferably 1.01 to 2.02-fold by mole, relative to thetheoretical mole required to prepare the “transition metal complex”.

While the amount of the “transition metal complex” to be used variesdepending on the reaction container, the style of the reaction, and thelike, it is, for example, about 1.0-about 0.00001 mol, per 1 mol of thesubstrate compound (I) or a salt thereof.

In the “asymmetric reductive amination reaction” of Step A-X, anadditive such as a base, an acid, a salt and the like may be added, ifnecessary. The additive may be used in a mixture of two or more kindsthereof. The additive may be added to a reaction container before orduring the “asymmetric reductive amination reaction”.

Examples of the base which may be added to the “asymmetric reductiveamination reaction” system of Step A-X include inorganic bases andorganic bases.

Examples of the inorganic base include alkali metal hydroxides such aslithium hydroxide, potassium hydroxide, sodium hydroxide, cesiumhydroxide and the like; alkali metal alkoxides having 1 to 6 carbonatoms such as lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide, lithiumpropoxide, sodium propoxide, potassium propoxide, lithium isopropoxide,sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide andthe like; alkali metal thioalkoxides having 1 to 6 carbon atoms such assodium thiomethoxide and the like; carbonates such as sodium carbonate,potassium carbonate, cesium carbonate and the like; hydrogencarbonatessuch as sodium hydrogencarbonate, potassium hydrogencarbonate and thelike; acetates such as sodium acetate, potassium acetate and the like;phosphates such as tripotassium phosphate, sodium phosphate and thelike; and monohydrogen phosphates such as potassium monohydrogenphosphate, sodium monohydrogen phosphate and the like.

Examples of the organic base include aliphatic amine as such astrimethylamine, triethylamine, N-methylmorpholine,N,N-diisopropylethylamine, diethylamine, diisopropylamine,cyclohexylamine, ethylenediamine and the like; aromatic amines such aspyridine, picoline, N,N-dimethylaniline and the like; and basic aminoacids such as arginine, lysine, ornithine and the like.

While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (A-c) or a saltthereof. The base can also be used as a solvent.

Examples of the acid which may be added to the “asymmetric reductiveamination reaction” system of Step A-X include mineral acids(specifically hydrofluoric acid, hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoricacid, phosphorous acid, carbonic acid, bicarbonic acid and the like);carboxylic acids (i.e., compounds having one or more carboxy groups;specifically formic acid, acetic acid, trifluoroacetic acid, benzoicacid, salicylic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid and the-like);acidic amino acids (specifically aspartic acid, glutamic acid and thelike); and sulfonic acids (i.e., compounds having one or more sulfogroups; specifically methanesulfonic acid, trifluoromethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acidand the like). Where necessary, the acid may be used in a mixture of twoor more kinds thereof.

While the amount of the acid to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01mol or more, per 1 mol of the substrate compound (A-c) or a saltthereof. The acid can also be used as a solvent.

Examples of the salt which may be added to the “asymmetric reductiveamination reaction” system of Step A-X include salts which contain theabove-mentioned “acid” as an acid component, in addition to saltsexemplified as the above-mentioned “inorganic base”.

While the amount of the salt to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 0.01to 100 mol, per 1 mol of the substrate compound (I) or a salt thereof.

The “asymmetric reductive amination reaction” of Step A-X is generallycarried out in a solvent. The solvent is not particularly limited aslong as it does not inhibit the reaction and can dissolve the rawmaterial compound, organic metal complex and additive, and examplesthereof include ethers such as diethyl ether, diisopropyl ether,tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane,methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane,1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole and the like;alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol,n-butanol, 2-butanol, t-butyl alcohol, 3-methyl-1-butanol,2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol,2-ethoxyethanol, ethylene glycol and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene, cumene, chlorobenzene and the like;saturated hydrocarbons such as hexane, heptane, pentane, cyclohexane,methylcyclohexane, isooctane, petroleum ether and the like; amides suchas N,N-dimethylformamide, N,N-dimethylacetamide, formamide,hexamethylphosphoramide, N-methylpyrrolidone,1,3-dimethyl-2-imidazolidinone and the like; halogenated hydrocarbonssuch as chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane and the like; nitriles such as acetonitrile,propionitrile and the like; sulfoxides such as dimethyl sulfoxide andthe like; sulfones such as dimethylsulfone, sulfolane and the like;ketones such as acetone, ethyl methyl ketone, methyl isopropyl ketone,methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate compound (A-c) or a saltthereof, and the like. The reaction can be carried out nearly without asolvent or in a solvent in an amount of 100 parts by weight or less per1 part by weight of the substrate compound (A-c) or a salt thereof,preferably in a solvent in an amount of about 2-about 100 parts byweight per 1 part by weight of the substrate compound (A-c) or a saltthereof.

The temperature in the “asymmetric reductive amination reaction” of StepA-X is generally −30 to 160° C., preferably 0 to 120° C., morepreferably 10 to 80° C. The reaction time is generally 0.1 to 120 hr,preferably 1 to 72 hr.

Compound (III) or a salt thereof obtained in the “asymmetric reductiveamination reaction” may be purified according to a means known per se(e.g., fractional recrystallization method, chiral column method,diastereomer salt method).

As the most preferable embodiment, a compound represented by the formula(A-c) is2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide;and

an optically active form of a compound represented by the formula (III)is2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide.

Step A-X in Production Method (AX) in the most preferable embodiment areexplained in detail below.

The “transition metal complex” used as a catalyst in “asymmetricreductive amination reaction” of Step A-X in the most preferableembodiment is particularly preferably an iridium complex.

The ligand for the “iridium complex” is preferably a diphosphine ligand;more preferred are 2,4-bis(diphenylphosphino)pentane (SKEWPHOS),SKEWPHOS derivative having 1 to 5 substituents such as a C₁₋₆ alkylgroup and the like on the benzene ring(s) bonded to the phosphorus atomof SKEWPHOS, 4,12-bis(diphenylphosphino)-[2,2]-paracyclophane(PhanePHOS), substituted-1,1′-bisphosphoranoferrocene (Ferrocelane) and1-[2-(disubstituted-phosphino)ferrocenyl]ethyl-disubstituted-phosphine(Josiphos); further more preferred are 2,4-bis(diphenylphosphino)pentane(SKEWPHOS) and SKEWPHOS derivative having 1 to 5 substituents such as aC₁₋₆ alkyl group and the like on the benzene ring(s) bonded to thephosphorus atom of SKEWPHOS; and particularly preferred ispentane-2,4-diylbis(bis(4-(tert-butyl)phenyl)phosphine), and use of theoptically active form thereof, i.e.,(R,R)-pentane-2,4-diylbis(bis(4-(tert-butyl)phenyl)phosphine) leads toproduction of the optically active form in the most preferableembodiment (compound (III) is (R)-form).

The “iridium complex” is preferably prepared just before using, bymixing a “ligand” and the other iridium complex as a iridium metalsource in a solvent, before addition of hydrogen gas. During preparingjust before using, the iridium complex is preferably coexistent with thesubstrate compound (A-c) or a salt thereof and an ammonium salt as anamine source. The solvent used in the preparation just before using ispreferably the same solvent as used in the subsequent “asymmetricreductive amination reaction”. The temperature of the preparation of the“iridium complex” just before using is generally 10 to 80° C.; morepreferably 30 to 60° C.: particularly preferably 35 to 55° C. The timeof the preparation of the “iridium complex” just before using isgenerally 30 to 360 min; more preferably 60 to 120 min. The procedure ofthe preparation of the “iridium complex” just before using is preferablycarried out under an inert gas atmosphere such as argon or nitrogen.

Preferable examples of the “other iridium complex as a iridium metalsource” include bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate,chloro(1,5-cyclooctadiene)iridium(I) (dimer),bis(1,5-cyclooctadiene)iridium(I)tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,iodo(1,5-cyclooctadiene)iridium(I) (dimer),(1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) and(acetylacetonato)(1,5-cyclooctadiene)iridium(I); and particularlypreferred is chloro(1,5-cyclooctadiene)iridium(I) (dimer).

The acid to be used for forming an ammonium salt used in the “asymmetricreductive amination reaction” is preferably an optionally substitutedsalicylic acid. The most preferable ammonium salt is ammoniumsalicylate. The amount of the ammonium salicylate to be added in the“asymmetric reductive amination reaction” is preferably 1.1 to 5equivalent, more preferably 2 to 4 equivalent, relative to the substratecompound (A-c) or a salt thereof.

Preferable examples of the solvent in the “asymmetric reductiveamination reaction” include tetrahydrofuran, 1,4-dioxane, methanol,isopropyl alcohol, 2-methyl-2-butanol and toluene, and particularlypreferred is tetrahydrofuran.

In the “asymmetric reductive amination reaction”, an additive may beadded. Preferable examples of the additive include water, zinc chloride,lithium chloride and terpyridine, and particular preferred is water.

When water is added to the “asymmetric reductive amination reaction”system, the amount is limited to small amount so that the waterconcentration in the reaction solution is 4000 ppm or less, preferably1000 to 3000 ppm; most preferably 1500 to 2500 ppm.

In the “asymmetric reductive amination reaction”, the hydrogen pressureis preferably 8 to 80 atm, more preferably 4 to 80 atm.

In the “asymmetric reductive amination reaction”, the reactiontemperature is preferably 30 to 60° C., more preferably 35 to 55° C.

In the “asymmetric reductive amination reaction”, the reaction time ispreferably 12 to 50 hr; more preferably 20 to hr.

Compound (III) or a salt thereof in the most preferable embodiment maybe purified according to a means known per se (e.g., fractionalrecrystallization method, chiral column method, diastereomer saltmethod).

In order to obtain the above-mentioned compound (III) or a salt thereofwith high optical purity, it is preferably purified by a fractionalrecrystallization method or a diastereomer salt method. Particularly,compound (III) or a salt thereof is preferably purified bycrystallization of the diastereomer salt with optically activedi-p-toluoyl-tartaric acid (preferably di-p-toluoyl-(D)-tartaric acidwhen the above-mentioned compound (III) is (R)-form) or optically activemandelic acid (preferably (S)-mandelic acid when the above-mentionedcompound (III) is (R)-form), particularly preferably crystallization ofthe diastereomer salt with optically active mandelic acid (preferably(S)-mandelic acid when the above-mentioned compound (III) is (R)-form).

[Production Method (B)]

Compound (V) or a salt thereof can be produced by reacting compound(III) or a salt thereof obtained in Production Method (A) with compound(IV) or a salt thereof, in order to form an amide bond, according toProduction Method (B) shown in the following scheme.

Production Method (B)

wherein each symbol is as defined above.

Compound (IV) or a salt thereof can be produced, for example, accordingto the method described in WO 2009-006389.

While the amount of compound (IV) or a salt thereof to be used in themethod “forming an amide bond” in the Production Method (B) variesdepending on the reaction condition, it is generally 0.5 to 30 mol,preferably 0.9 to 2 mol, per 1 mol of compound (III) or a salt thereof.

In the above-mentioned Production Method (B), while the salt of compound(III) obtained in Production Method (A) may be directly used in thecondensation reaction, it is preferably converted to the free form byreacting with a base. Examples of the base include inorganic bases andorganic bases.

Examples of the inorganic base include alkali metal hydroxides such aslithium hydroxide, potassium hydroxide, sodium hydroxide, cesiumhydroxide and the like; alkali metal alkoxides having 1 to 6 carbonatoms such as lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide, lithiumpropoxide, sodium propoxide, potassium propoxide, lithium isopropoxide,sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide andthe like; alkali metal thioalkoxides having 1 to 6 carbon atoms such assodium thiomethoxide and the like; carbonates such as sodium carbonate,potassium carbonate, cesium carbonate and the like; hydrogencarbonatessuch as sodium hydrogencarbonate, potassium hydrogencarbonate and thelike; acetates such as sodium acetate, potassium acetate and the like;phosphates such as tripotassium phosphate, sodium phosphate and thelike; and monohydrogen phosphates such as potassium monohydrogenphosphate, sodium monohydrogen phosphate and the like.

Examples of the organic base include aliphatic amines such astrimethylamine, triethylamine, N-methylmorpholine,N,N-diisopropylethylamine, diethylamine, diisopropylamine,cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene andthe like; aromatic amines such as pyridine, picoline,N,N-dimethylaniline and the like; and basic amino acids such asarginine, lysine, ornithine and the like. These bases may be used in amixture in an appropriate ratio.

As the base used in the reaction for the conversion of the salt ofcompound (III) to the free form, sodium hydrogencarbonate isparticularly preferable.

While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally 0.5 to 100mol, preferably 1.0 to 10 mol, particularly preferably 1.5 to 4 mol, per1 mol of the substrate salt of compound (III). When the base is aliquid, it can also be used as a solvent.

While the reaction for the conversion of the salt of compound (III) tothe free form may be carried out without a solvent, it is generallycarried out in a solvent. The solvent is not particularly limited aslong as it does not inhibit the reaction and can dissolve the rawmaterial compound and additive, and examples thereof include ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenylether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, t-butyl alcohol,3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.As the solvent used in the reaction for the conversion the salt ofcompound (III) to the free form, ethers, alcohols and nitriles arepreferable, and acetonitrile is particularly preferable.

The solvent is preferably used as a mixed solvent. When a nitrile(preferably acetonitrile) is used as a solvent, it is particularlypreferably mixed with water.

The amount of the solvent to be used is appropriately determineddepending on the solubility of the substrate salt of compound (III), andthe like. For example, when the salt of compound (III) is a salt withmandelic acid, and a nitrile (preferably acetonitrile) is used as asolvent, the reaction can be carried out nearly without a solvent or ina solvent in an amount of 100 parts by weight or less per 1 part byweight of the substrate salt of compound (III), preferably in a solventin an amount of 5 to 30 parts by weight per 1 part by weight of thesubstrate salt of compound (III).

The temperature in the reaction for the conversion to the free form isgenerally −10 to 80° C., preferably 0 to 40° C. The reaction time isgenerally 0.01 to 2 hr, preferably 0.1 to 1 hr.

Compound (III) obtained in the reaction for the conversion to the freeform may be isolated and purified according to a means known per se(concentration, concentration under reduced pressure, solventextraction, crystallization, recrystallization, phase transfer,chromatography and the like). Alternatively, the reaction solution maybe used directly in the condensation reaction with compound (IV) or asalt thereof.

The method “forming an amide bond” in the Production Method (B) can becarried out according to a method known per se such as the methoddescribed in Tetrahedoron, vol 61, page 10827, 2005.

The method “forming an amide bond” is preferably carried out by themethod using compound (IV) wherein X is a hydroxy group and a condensingagent.

Examples of the “condensing agent” include carbodiimide condensingagents (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

-   1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride    N,N′-dicyclohexylcarbodiimide;-   N,N′-diisopropylcarbodiimide);-   imidazole condensing agents (N,N′-carbonyldiimidazole;-   1,1′-carbonyldi(1,2,4-triazole); triazine condensing agents    (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride    n hydrate;-   (4,6-dimethoxy-1,3,5-triazin-2-yl)-(2-octoxy-2-oxoethyl)dimethylammonium    trifluoromethanesulfonate);-   phosphonium condensing agents    (1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate;-   1H-benzotriazol-1-yloxytripyrrolidinophosphonium    hexafluorophosphate;-   (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate;-   chlorotripyrrolidinophosphonium hexafluorophosphate;    bromotris(dimethylamino)phosphonium hexafluorophosphate;-   3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one);-   uronium condensing agents    (0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate;-   O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;-   O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate;-   S-(1-oxide-2-pyridyl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate;-   O-[2-oxo-1(2H)-pyridyl]-N,N,N′,N′-tetramethyluronium    tetrafluoroborate;-   {{(([(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium    hexafluorophosphate); and-   halouronium condensing agents (2-chloro-1,3-dimethylimidazolinium    hexafluorophosphate;-   1-(chloro-1-pyrrolidinyl methylene)pyrrolidinium    hexafluorophosphate;-   2-fluoro-1,3-dimethylimidazolinium hexafluorophosphate;    fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate).

As the “condensing agent”, carbodiimide condensing agents arepreferable, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideand N,N′-dicyclohexylcarbodiimide are more preferable, andN,N′-dicyclohexylcarbodiimide is particularly preferable.

While the amount of the “condensing agent” to be used varies dependingon the kinds of the condensing agent and solvent and the other reactioncondition, it is generally 0.8 to 10 mol, preferably 0.9 to 2 mol, per 1mol of compound (IV) or a salt thereof.

In the reaction by the method “forming an amide bond” in ProductionMethod (B), an additive is preferably used.

Examples of the “additive” include 1-hydroxybenzotriazole,1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide and carbonic acidN,N′-disuccinimidyl. Preferred is 1-hydroxybenzotriazole.

While the amount of the “additive” to be used varies depending on thekinds of the additive, condensing agent and solvent and the otherreaction condition, it is generally 0.01 to 1.0 mol, preferably 0.05 to0.5 mol, per 1 mol of compound (IV) or a salt thereof.

While the reaction by the method “forming an amide bond” in ProductionMethod (B) may be carried out nearly without a solvent, it is generallycarried out in a solvent. The solvent is not particularly limited aslong as it does not inhibit the reaction and can dissolve the rawmaterial compound and additive, and examples thereof include ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenylether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane, anisole and the like; alcohols such as methanol,ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, t-butyl alcohol,3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol,2-methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like;aromatic hydrocarbons such as benzene, toluene, xylene, cumene,chlorobenzene and the like; saturated hydrocarbons such as hexane,heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleumether and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, formamide, hexamethylphosphoramide,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like;halogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane and the like; nitriles such asacetonitrile, propionitrile and the like; sulfoxides such as dimethylsulfoxide and the like; sulfones such as dimethylsulfone, sulfolane andthe like; ketones such as acetone, ethyl methyl ketone, methyl isopropylketone, methyl butyl ketone and the like; esters such as ethyl acetate,isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate,methyl acetate, ethyl formate and the like; nitromethane; water and thelike. These solvents may be used in a mixture in an appropriate ratio.As the solvent used in the reaction by the method “forming an amidebond” in Production Method (B), amides are preferable, andN,N-dimethylacetamide is more preferable.

The amount of the solvent to be used is appropriately determineddepending on the solubility of compound (III) or a salt thereof, andcompound (IV) or a salt thereof, and the like. For example, whenN,N-dimethylacetamide is used as a solvent, the reaction can be carriedout nearly without a solvent or in a solvent in an amount of 100 partsby weight or less per 1 part by weight of compound (III) or a saltthereof, preferably in a solvent in an amount of 1 to 20 parts by weightper 1 part by weight of the substrate compound (III) or a salt thereof.

The temperature in the reaction by the method “forming an amide bond” isgenerally −10 to 120° C., preferably 0 to 60° C. The reaction time isgenerally 0.1 to 48 hr, preferably 0.5 to 16 hr.

Compound (V) or a salt thereof obtained in the reaction by the method“forming an amide bond” in Production Method (B) may be isolated andpurified according to a means known per se (concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like).

The “isolation and purification” means is preferably crystallization,particularly preferably crystallization from a mixed solvent ofn-butanol and water.

The isolated and purified compound (V) or a salt thereof is preferablyfurther purified by recrystallization to give the compound with highpurity. The solvent for the “recrystallization” is particularlypreferably dimethyl sulfoxide, 2-propanol, or a mixed solvent of thesolvent and water.

[Production Method (C)]

The asymmetric hydrogenation reaction in the presence of a transitionmetal complex in the present invention can be applied to the productionof an optically active amine compound, in addition to the production ofcompound (II) or a salt thereof.

Preferable examples of the production of an optically active aminecompound are shown below.

A compound represented by the formula (B):

whereinAr^(X) and Ar^(Y) are each independently an optionally substituted C₆₋₁₄aryl group;Ar^(Z) is an optionally substituted C₆₋₁₄ aryl group, or an optionallysubstituted heterocyclic group;R^(x) is an optionally substituted C₁₋₆ alkyl group;R^(x) and Ar^(Z) in combination optionally form an optionallysubstituted 8-14-membered fused polycyclic together with the adjacentatom; andthe carbon atom marked with * is an asymmetric carbon atom, or a saltthereof, can be obtained by subjecting a compound represented by theformula (A):

wherein each symbol is as defined above,or a salt thereof, to an asymmetric hydrogenation reaction in thepresence of a transition metal complex having a trivalent phosphineligand.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples and Examples, which are merelyexemplified and not to be construed as limitative, and the invention maybe changed within the scope of the present invention.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C.

In the reaction scheme, s/c means substrate-catalyst ratio (substrate(mol)/catalyst (mol)), and s/s means substrate-solvent ratio (solvent(ml)/substrate (g)).

The chemical yield is an isolated yield (mol/mol %) or a yield measuredby high-performance liquid chromatography. The optical purity(asymmetric yield) of an optically active form was evaluated byenantiomeric excess (% e.e.). The enantiomeric excess was calculatedaccording to the following formula.

Enantiomeric excess (% e.e.)=100×[(R)−(S)]/[(R)+(S)] or100×[(S)−(R)]/[(R)+(S)] wherein (R) and (S) are each an area of eachenantiomer measured by high-performance liquid chromatography.

In addition, the amount of solvent used for chromatography is shown by %by volume, and the amount of the other is shown by % by weight.

Regarding enantiomer, the compound wherein the absolute configuration isdetermined is described as R or S. For the compound wherein the absoluteconfiguration is not determined, the enantiomeric excess was calculatedfrom the results of high-performance liquid chromatography (opticalpurity).

Enantiomeric excess (% e.e.)=100×[(front peak)−(back peak)]/[(frontpeak)+(back peak)]

In proton NMR spectrum, broad and unidentified protons such as OH and NHprotons and the like are not described in data.

The abbreviations used in the specification mean the following technicalterm or the structure.

-   s: singlet-   d: doublet-   t: triplet-   q: quartet-   m: multiplet-   br: broad-   J: coupling constant-   Hz: hertz)-   CDCl₃: deuterochloroform-   DMSO-ds: deuterodimethyl sulfoxide-   CD₃OD: deuteromethanol-   ¹H NMR: proton nuclear magnetic resonance-   ¹³C NMR: ¹³Cnuclear magnetic resonance-   ¹⁹F NMR: ¹⁹Fnuclear magnetic resonance-   ³¹P NMR: ³¹Pnuclear magnetic resonance-   [RhCl(cod)]₂: chloro(1,5-cyclooctadiene)rhodium(I) dimer-   [Rh(cod)₂]OTf: bis(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   [Rh(cod) (R)—(S)-josiphos]OTf:    (1,5-cyclooctadiene)((R)-(−)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine)rhodiu    m(I) trifluoromethanesulfonate-   [Rh(nbd) (R)—(S)-josiphos]BF₄:    {(R)-(−)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine}(norbo    rnadiene)rhodium(I) tetrafluoroborate-   [Rh(cod) (S,S)-skewphos]OTf:    ((2S,4S)-(−)-2,4-bis(diphenylphosphino)pentane)(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   [Rh (nbd) (S,S)-bisP*]BF₄:    {(S,S)-1,2-bis-(t-butyl(methyl)phosphino)ethane}(norbornadiene)rhodium(I)    tetrafluoroborate-   [Rh(cod) (R,R)-dipamp]BF₄:    (R,R)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I)    tetrafluoroborate-   [Rh(cod) (S)-xyl-binap]OTf:    {(S)-(−)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   RuCl₂{(R)-binap}:    dichloro[(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II)-   RuCl₂{(R)-binap}{R,R-dpen}:    dichloro[(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]{(1R,2R)-(+)-1,2-diphenylmethanediamine}ruthenium(II)-   RuCl₂{(R)-binap}{R,R-dach}:    dichloro[(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]{(1R,2R)-(+)-1,2-diaminocyclohexane}ruthenium(II)-   RuCl₂{(R)-binap}{R-daipen}:    dichloro{(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl}[(2R)-(−)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)-   RuCl₂{(R)-xyl-binap}{R,R-dpen}:    dichloro{(R)-(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}{(1R,2R)-(+)-1,2-diphenylmethanediamine}ruthenium(II)-   RuCl₂{(R)-xyl-binap}{R,R-dach}:dichloro{(R)-(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}{(1R,2R)-(+)-1,2-diaminocyclohexane}ruthenium(II)-   RuCl₂{(R)-xyl-binap}{R-daipen}:    dichloro{(R)-(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2R)-(−)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)-   [Ir(cod)₂]BARF: bis(1,5-cyclooctadiene)iridium(I)    tetrakis[3,5-bis(trifluoromethyl)phenyl]borate-   [Ir(cod)₂]BF₄: bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate-   [IrCl(cod)]₂: chloro(1,5-cyclooctadiene)iridium(I) dimer-   [IrOMe(cod)]₂: (1,5-cyclooctanediene)methoxyiridium(I) dimer-   Ir(acac) (cod): (acetylacetonato) (1,5-cyclooctanediene)iridium(I)-   Pd(OCOCF₃)₂: palladium(II) trifluoroacetate-   Pd(OAC)₂: palladium(II) acetate-   (R)—(S)-Josiphos (SL-J001-1):    (R)-(−)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine    SL-M001-1:    (αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene-   SL-W001-1:    (R)-1-[(R)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine-   SL-W002-1:    (R)-1-[(R)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine-   SL-W003-1:    (R)-1-[(R)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethyldicyclohexylphosphine-   SL-T001-1:    (S)-1-diphenylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl-methyl]ferrocene-   SL-T002-1:    (S)-1-dicyclohexylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-dicyclohexylphosphinophenyl-methyl]ferrocene-   SL-J004-1:    (R)-1-[(1S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine-   (S) (R)-SL-J002-02:    (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J502-1:    (R)-1-[(S)-2-(di-t-butylphosphino)ferrocenyl]ethyldiphenylphosphine-   (R) (S)-SL-J009-1:    (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J005-1:    (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine-   (R) (S)-SL-J011-1:    (R)-1-[(S)-2-[di-(4-trifluoromethylphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R)(S)-SL-J013-1:    (R)-1-[(S)-2-[di-(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J014-1:    (R)-1-[(S)-2-[di-(4-fluorophenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J212-1:    (R)-1-[(S)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J216-1:    (R)-1-[(S)-2-(di-1-naphthylphosphino)ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J202-1:    (R)-1-[(S)-2-[di-(4-methoxyphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R)(S)-SL-J203-1:    (R)-1-[(S)-2-[di-(3,5-di-t-butyl-4-methoxyphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R) (S)-SL-J210-1:    (R)-1-[(S)-2-[di-(3,5-di-trifluoromethylphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (S)(R)-SL-J210-2:    (S)-1-[(R)-2-[di-(3,5-di-trifluoromethylphenyl)phosphino]ferrocenyl]ethyldi-t-butylphosphine-   (R,R)-Skewphos: (2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane-   (R)-BINAP: (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   (R)-xylyl-BINAP:    (R)-(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl-   (S)-H8-BINAP:    (S)-(−)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-   (R,R)-Me-Duphos: (−)-1,2-bis[(2R,5R)-2,5-dimethylphosphorano]benzene-   (R,R)-Et-Duphos: (−)-1,2-bis[(2R,5R)-2,5-diethylphosphorano]benzene-   (R,R)-iPr-Duphos:    (−)-1,2-bis[(2R,5R)-2,5-diisopropylphosphorano]benzene-   (R,R)-Ph-BPE: (−)-1,2-bis((2R,5R)-2,5-diphenylphosphorano)ethane-   (R)-Phanephos:    (R)-(−)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane-   (S)-xyl-Phanephos:    (S)-(+)-4,12-bis(di(3,5-xylyl)phosphino)-[2.2]-paracyclophane-   (S,S)-Et-Ferrotane:    (−)-1,1′-bis[(2S,4S)-2,4-diethylphosphotano]ferrocene-   (R,R)-DIPAMP: (R,R)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane-   (R,R)-Quinox-P*:    (R,R)-(−)-2,3-bis(t-butylmethylphosphino)quinoxaline-   (S)-DTBM-Segphos:    (S)-(+)-5,5′-bis[di(3,5-di-t-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole-   (R)-C3-Tunephos:    (R)-(−)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonin-   (S)-MeO-BIPHEP:    (S)-(−)-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl-   (S)-ShiP: phenyl-[(S)-1,1-spirobiindane-7,7-diyl]phosphite-   (S)-MOP: (S)-(−)-2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl-   (R)-QuINAP: (R)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline-   (S)-Monophos:    (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine-   (S)-Me-Monophos:    (S)-(+)-(2,6-dimethyl-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine-   (R,R)-Taddol-type:    (3aR,8aR)-(−)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl)dimethylamine-   (S)-BnMe:    (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)benzyl(methyl)amine-   (S,R,R)-alpha-phenethyl:    (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)bis[(1R)-1-phenylethyl]amine-   (S)-Et-Monophos:    (S)-(+)-(2,6-dimethyl-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)diethylamine-   (S)-Morphos:    (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)morpholine-   (S)-alpha-phenethylH:    (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)[(1R)-1-phenylethyl]amine-   (S)-Pipphos:    (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)piperidine-   (S)-H8-Monophos:    (S)-(+)-(8,9,10,11,12,13,14,15-octahydro-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine-   (R,R)-cataciumM(R):    (−)-2,3-bis[(2R,5R)-2,5-dimethylphosphorano]maleic anhydride-   cataASium T3:    (+)-{4-[(1R,4S)-3-(diphenylphosphino)-1,7,7-trimethylbicyclo[2.2.1]heptenehept-2-en-2-yl]-2,5-dimethyl-3-thienyl}bis(3,5-dimethylphenyl)phosphine-   (R,R)-Norphos:    (2R,3R)-(−)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene-   (R)-iPr-PHOX:    (R)-(+)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline-   DMF: N,N-dimethylformamide-   CPME: cyclopentyl methyl ether-   DME: dimethyl ether-   MeCN: acetonitrile-   AcOH: acetic acid-   EtOH: ethanol-   NBS: N-bromosuccinimide-   Et₃N: triethylamine-   EDC: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-   hydrochloride-   HOBT: 1-hydroxybenzotriazole-   DMAc: N,N-dimethylacetamide-   1-BuOH: n-butanol-   IPA: 2-propanol-   DMSO: dimethylsulfooxide-   THF: tetrahydrofuran-   DCM: dichloromethane-   MeOH: methanol-   p-TsOH: p-toluenesulfonic acid-   TMSCl: chlorotrimethylsilane-   DCE: 1,2-dichloroethane-   Et₃SiH: triethylsilane-   (S)-MA: (S)-mandelic acid-   MS4A: molecular sieve 4A-   TMEDA: tetramethylethylene diamine-   AHN: ammonium 2-hydroxynicotinate-   APC: ammonium picolinate-   ATFA: ammonium trifluoroacetate-   (−)-CSA: (−)-10-camphorsulfonic acid

In the following Reference Examples and Examples, the nuclear magneticresonance spectrum (NMR) was measured under the following conditions.

¹H nuclear magnetic resonance spectrum (¹H-NMR): BRUKER AVANCE 500 (500MHz) manufactured by Bruker Corporation, internal standard material:tetramethylsilane

¹³C nuclear magnetic resonance spectrum (¹³C-NMR): BRUKER AVANCE 500(125 MHz) manufactured by Bruker Corporation, internal standardmaterial: CDCl₃

¹⁹F nuclear magnetic resonance spectrum (¹⁹F-NMR): BRUKER AVANCE 500(202 MHz) manufactured by Bruker Corporation, external standardmaterial: trifluoroacetic acid

³¹P nuclear magnetic resonance spectrum (³¹P-NMR): BRUKER AVANCE 500(471 MHz) manufactured by Bruker Corporation, external standardmaterial: 85%-H₃PO₄ aqueous solution

Reference Example 1 Synthesis of2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-1,3-thiazole-5-carboxylic acid (24.7 g), 1,2-dimethoxyethane(43 mL), N,N-dimethylformamide (0.047 g) and oxalyl chloride (17.8 g)were put into a four-necked eggplant flask (100 mL), and the mixture wasstirred at room temperature for 2 hr (Reaction Solution 1). Separately,5-chloro-4-(trifluoromethyl)pyridin-2-amine hydrochloride (30.0 g),acetonitrile (96 mL) and pyridine (30.8 g) were put into a four-neckedeggplant flask (500 mL), and the mixture was cooled to about 5° C.(Reaction Solution 2). Reaction Solution 1 was added to ReactionSolution 2 at 35° C. or lower, and 1,2-dimethoxyethane (15 mL) was addedthereto. The mixture was stirred at room temperature for 1 hr, warmed toabout 50° C., and stirred for 1 hr. Water (210 mL) was added thereto atabout 50° C., and the mixture was cooled to room temperature, and wasstirred for 30 min. The crystallized substance was collected byfiltration, washed with a mixed solvent of acetonitrile (22.5 mL) andwater (67.5 mL), washed with water (180 mL), and dried under reducedpressure at 50° C. to give the title compound. pale-brown powder, 43.4g, yield 96%, purity 99.0% (HPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: Inertsil ODS-3 5 μm, 4.6 mm i.d.×150 mmUV detection wavelength: 254 nmcolumn temperature: 25° C.mobile phase:

TABLE 1 acetonitrile/0.025 acetonitrile/0.025 mol/L aqueous potassiummol/L aqueous potassium dihydrogenphosphate dihydrogenphosphate solution(6:4) solution (8:2)  0.00 min. 100%  0%  5.00 min. 100%  0% 10.00 min. 0% 100% 50.00 min.  0% 100%flow rate: 1.0 mL/minretention time: 8.9 min (the title compound)

¹H NMR (DMSO-d₆) δ 2.67 (s, 3H), 8.58 (s, 1H), 8.80 (s, 1H), 9.00 (s,1H), 12.00 (s, 1H). HRMS (ESI) calcd for C₁₂HeClF₃N₃O₂S [(M+H)⁺]349.9972, found 349.9977. m.p. 165° C.

Reference Example 2 Synthesis of(E)-2-(1-(benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(40.0 g), ethanol (200 mL), benzhydrylamine (23.1 g) and acetic acid(1.96 mL) were put into a four-necked eggplant flask (300 mL) equippedwith Dean-Stark trap, and the mixture was heated under reflux for 6.5hr. The mixture was cooled to room temperature, and stirred for 1 hr.The crystallized substance was collected by filtration, washed withethanol (100 mL), and dried under reduced pressure at 50° C. to givecrystals. The obtained all crystals (59.4 g) and toluene (300 mL) wereput into four-necked eggplant flask (2 L), and the mixture was heatedunder reflux until 60 mL of the solvent was evaporated. To the residuewas added toluene (60 mL), and the mixture was heated under reflux untilevaporation of 60 mL of the solvent. The procedure was performedthreetimes in total. N-heptane (900 mL) was added thereto at about 80°C., and the mixture was cooled to room temperature, and stirred for 1hr. The crystallized substance was collected by filtration, washed witha mixed solvent of toluene (40 mL) and n-heptane (200 mL), and driedunder reduced pressure at 60° C. to give the title compound. whitepowder, 51.4 g, yield 87%, purity 99.7% (HPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: Inertsil C8-4, HP 3 μm, 4.6 mm i.d.×150 mmUV detection wavelength: 254 nmcolumn temperature: 25° C.mobile phase:

TABLE 2 0.005 mol/L aqueous potassium dihydrogenphosphate solution/0.005 mol/L aqueous dipotassium hydrogenphosphate solution (1:1)acetonitrile  0.00 min. 45% 55%  2.00 min. 45% 55% 25.00 min. 20% 80%30.00 min. 20% 80%flow rate: 1.0 mL/minretention time: 20.8 min (the title compound)

¹H NMR (CDCl₃) δ 2.46 (s, 3H), 5.90 (s, 1H), 7.24 (m, 2H), 7.33 (m, 4H),7.45 (m, 4H), 8.36 (s, 1H), 8.43 (brs, 1H), 8.44 (s, 1H), 8.69 (s, 1H).HRMS (ESI) calcd for C₂₅H₁₉ClF₃N₄OS [(M+H)+]515.0915, found 515.0914.m.p. 175° C.

Example 1 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

(E)-2-(1-(Benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(45.0 g), [Ir(cod)₂]BARF (0.167 g) and (S)-Monophos (0.104 g) were putinto an autoclave (1 L). The atmosphere in the autoclave wasdecompressed, and replaced with argon, and dehydrated dichloromethane(500 mL) was added thereto. The mixture was stirred at room temperaturefor 10 min, and hydrogen was fed into the autoclave until 0.65 MPa. Themixture was heated to about 50° C., hydrogen was fed into the autoclaveuntil 0.80 MPa, and the mixture was stirred for 24 hr. The mixture wascooled to room temperature, the hydrogen was released, and theatmosphere was replaced with argon. The mixture was concentrated underreduced pressure, acetonitrile (135 mL) was added thereto, and themixture was concentrated under reduced pressure. Acetonitrile (135 mL)and water (22.5 mL) were added thereto, and then N-bromosuccinimide(17.1 g) was added thereto at room temperature, and the mixture wasstirred for 18 hr. Triethylamine (9.73 g) and acetonitrile (900 mL) wereadded thereto at room temperature, and then (S)-mandelic acid (16.0 g)dissolved in acetonitrile (270 mL) was added dropwise thereto at roomtemperature. The crystallized substance was collected by filtration,washed with acetonitrile (180 mL), and dried under reduced pressure at50° C. to give the title compound. white powder, 32.9 g, yield 75%,purity 99.9% (HPLC), optical purity 98.6% de (chiral HPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: L-column2 ODS, S-5 μm, 4.6 mm i.d.×250 mmUV detection wavelength: 220 nmcolumn temperature: 25° C.mobile phase:

TABLE 3 0.1 v/v % aqueous phosphoric acid solution acetonitrile  0.00min. 90% 10%  2.00 min. 90% 10% 30.00 min. 10% 90% 40.00 min. 10% 90%flow rate: 1.0 mL/minretention time: 14.9 min (the title compound)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CROWNPAK CR-I(+), S-5 μm, 3.0 mm i.d.×150 mmUV detection wavelength: 305 nmcolumn temperature: 25° C.mobile phase:

TABLE 4 0.5% aqueous perchloric acid solution acetonitrile  0.00 min.60% 40%  2.00 min. 60% 40% 15.00 min. 40% 60% 16.00 min. 10% 90% 20.00min. 10% 90%flow rate: 0.5 mL/minretention time: 5.2 min (R), 8.1 min (S)

¹H NMR (DMSO-d₆) δ 1.43 (d, J=6.5 Hz, 3H), 4.33 (m, 1H), 4.91 (s, 1H),7.25 (m, 1H), 7.32 (m, 1H), 7.40 (m, 1H), 8.59 (s, 1H), 8.73 (s, 1H),8.77 (s, 1H), 11.66 (brs, 1H). m.p. 152° C.

Example 2 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

Water (145 mL), sodium hydrogencarbonate (8.35 g), acetonitrile (145 mL)and2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (25.0 g) were put into a four-necked eggplant flask (500mL), and the mixture was stirred at room temperature for 15 min.Activated carbon SHIRASAGI A (2.5 g) was added thereto, and the mixturewas stirred at room temperature for 15 min. The activated carbon wasremoved by filtration, and washed with a mixed solvent of acetonitrile(12.5 mL) and water (12.5 mL). To the filtrate and washing was addedwater (250 mL) at room temperature, and the mixture was stirred at roomtemperature for 1 hr. The crystallized substance was collected byfiltration, washed with water (300 mL), and dried under reduced pressureat 50° C. to give the title compound. white powder, 15.1 g, yield 87%,purity 99.9% (HPLC). optical purity 98.6% ee (chiral HPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: L-column2 ODS, S-5 μm, 4.6 mm i.d.×250 mmUV detection wavelength: 220 nmcolumn temperature: 25° C.mobile phase:

TABLE 5 0.1 v/v% aqueous phosphoric acid solution acetonitrile  0.00min. 90% 10%  2.00 min. 90% 10% 30.00 min. 10% 90% 40.00 min. 10% 90%flow rate: 1.0 mL/minretention time: 14.9 min (the title compound)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CROWNPAK CR-I(+), S-5 μm, 3.0 mm i.d.×150 mmUV detection wavelength: 305 nmcolumn temperature: 25° C.mobile phase:

TABLE 6 0.5% aqueous perchloric acid solution acetonitrile  0.00 min.60% 40%  2.00 min. 60% 40% 15.00 min. 40% 60% 16.00 min. 10% 90% 20.00min. 10% 90%flow rate: 0.5 mL/minretention time: 5.2 min (R), 8.1 min (S)

¹H NMR (DMSO-d₆) δ 1.39 (d, J=7.0 Hz, 3H), 4.21 (q, J=7.0 Hz, 1H), 8.59(s, 1H), 8.70 (s, 1H), 8.76 (s, 1H), 11.59 (brs, 1H). HRMS (ESI) calcdfor C₁₂H₁₁ClF₃N₄OS [(M+H)⁺] 351.0289, found 351.0290. m.p. 154° C.

Example 3 Synthesis of6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide

1-Hydroxybenzotriazole monohydrate (1.31 g),6-amino-5-chloropyrimidine-4-carboxylic acid (8.16 g) and2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(15.0 g) and N,N-dimethylacetamide (75 mL) were put into a four-neckedeggplant flask (500 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (8.61 g) was added thereto, and the mixture was stirred atroom temperature for 4 hr. n-Butanol (75 mL) was added thereto at roomtemperature, and the mixture was heated to about 55° C. Water (180 mL)was added thereto, and the mixture was stirred for 40 min. Water (45 mL)was added thereto at about 55° C., and the mixture was cooled to roomtemperature, and stirred for 30 min. The crystallized substance wascollected by filtration, washed with water (150 mL), and dried underreduced pressure at 60° C. to give the title compound. white powder,19.1 g, yield 88%, purity 99.9% (HPLC). optical purity 96.1% ee (chiralHPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: Waters XTerra RP18, 5 μm, 3.9×150 mmUV detection wavelength: 254 nmcolumn temperature: 30° C.mobile phase:

TABLE 7 0.1 v/v % aqueous formic 0.1 v/v % formic acid- acid solutioncontaining acetonitrile  0.00 min. 80% 20%  1.00 min. 80% 20% 26.00 min.15% 85% 31.00 min. 15% 85%flow rate: 0.6 mL/minretention time: 16.0 min (the title compound)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CHIRALPAK IC-3, 3 μm, 4.6×150 mmUV detection wavelength: 277 nmcolumn temperature: 40° C.mobile phase: aqueous formic acid solution (pH 2.0)/acetonitrile=6/4flow rate: 1.0 mL/minretention time: 14.1 min (R), 16.7 min (S)

¹H NMR (DMSO-d₆) δ 1.59 (d, J=7.0 Hz, 3H), 5.35 (m, 1H), 7.41 (brs, 1H),7.81 (brs, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.76 (s, 1H), 8.78 (s, 1H),9.51 (d, J=8.0 Hz, 3H), 11.76 (s, 1H). HRMS (ESI) calcd forC₁₇H₁₃Cl₂F₃N₇O₂S [(M+H)⁺] 506.0175, found 506.0175. m.p. 206° C.

Example 4 Purification of6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide

6-Amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide(15.0 g), dimethyl sulfoxide (25.5 mL) and 2-propanol (102 mL) were putinto four-necked eggplant flask (200 mL), and the mixture was heated toabout 75° C. The insoluble substance was removed by filtration, andwashed with a mixed solvent of dimethyl sulfoxide (4.5 mL) and2-propanol (18 mL). To the filtrate and washing was added water (45 mL)at about 75° C., and the seed crystals of6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)pyrimidine-4-carboxamide(15.0 mg) was added thereto, and the mixture was stirred for 30 min. Themixture was cooled to about 45° C., and stirred for 1 hr. The mixturewas heated to about 75° C., and water (90 mL) was added thereto. Themixture was cooled to room temperature, and stirred for 1 hr. Thecrystallized substance was collected by filtration, washed with2-propanol (150 mL), and dried under reduced pressure at 60° C. to givethe title compound. white powder, 13.8 g, yield 91%, purity 99.9%(HPLC). optical purity 97.5% ee (chiral HPLC).

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: Waters XTerra RP18, 5 μm, 3.9×150 mmUV detection wavelength: 254 nmcolumn temperature: 30° C.mobile phase:

TABLE 8 0.1 v/v % aqueous formic 0.1 v/v % formic acid- acid solutioncontaining acetonitrile  0.00 min. 80% 20%  1.00 min. 80% 20% 26.00 min.15% 85% 31.00 min. 15% 85%flow rate: 0.6 mL/minretention time: 16.0 min (the title compound)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CHIRALPAK IC-3, 3 μm, 4.6×150 mmUV detection wavelength: 277 nmcolumn temperature: 40° C.mobile phase: aqueous formic acid solution (pH 2.0)/acetonitrile=6/4flow rate: 1.0 mL/minretention time: 14.1 min (R), 16.7 min (S)

¹H NMR (DMSO-d₆) δ 1.59 (d, J=7.0 Hz, 3H), 5.35 (m, 1H), 7.41 (brs, 1H),7.81 (brs, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.76 (s, 1H), 8.78 (s, 1H),9.51 (d, J=8.0 Hz, 3H), 11.76 (s, 1H). HRMS (ESI) calcd forC₁₇H₁₃C₂F₃N₇O₂S [(M+H)⁺] 506.0175, found 506.0175. m.p. 206° C.

Example 5 Synthesis of2-((1R)-1-(benzhydrylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

(E)-2-(1-(Benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(290.66 g), [Ir(cod)₂]BARF (1.44 g) and (S)-MONOPHOS (0.89 g) were putinto an autoclave (10 L). The atmosphere in the autoclave wasdecompressed until the pressure was decreased by −0.90 MPa or below, andthe pressure was recovered to about 0.1 MPa with argon. The procedureswere performed seven times in total. The pressure of the autoclave wasrecovered to normal pressure, and dehydrated dichloromethane (3 L) fororganic synthesis was fed thereto by argon pressure. The mixture wasstirred for 10 min. After stopping the stirring, hydrogen was fed intothe autoclave until the pressure was increased by 0.1 MPa, and thepressure was recovered to normal pressure. The procedures were performedten times in total. Hydrogen was fed into the autoclave until 0.90 MPa,and the mixture was stirred at the internal temperature of 50° C. for 23hr. The mixture was cooled to the internal temperature of about 20° C.,and the hydrogen was released. The atmosphere was replaced with argon,and the reaction solution was taken out. The reaction solution wasconcentrated under reduced pressure to give the title compound. brownoil, 304.77 g, yield 104.5%, HPLC area normalization 99.3%, opticalpurity 89.9% ee.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 6.9 min (the title compound), 9.3 min (the substrate)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 8.8 min (S), 14.3 min (R)

Example 6 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamidehydrobromide

(E)-2-(1-(Benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(5.00 g), [Ir(cod)₂]BARF (0.0247 g) and (S)-MONOPHOS (0.0154 g) were putinto an autoclave (120 mL). The atmosphere in the autoclave wasdecompressed, and the pressure was recovered with argon. The procedureswere performed seven times in total. The pressure of the autoclave wasrecovered to normal pressure, and dehydrated toluene (50 mL) for organicsynthesis was fed thereto by argon pressure. Hydrogen was fed into theautoclave until the pressure was increased by 0.1 MPa, and the pressurewas recovered to normal pressure. The procedures were performed tentimes in total. Hydrogen was fed into the autoclave until 1.20 MPa, andthe mixture was stirred at the internal temperature of 80° C. for 18 hr.The mixture was cooled to the internal temperature of about 20° C., thehydrogen was released, and the atmosphere was replaced with argon. Thereaction solution was stirred at near room temperature for 2 hr, and theinsoulble substance was removed by filtration, and washed with toluene(10 mL). To the filtrate and washing were added water (0.874 mL) andN-bromosuccinimide (1.73 g) at near room temperature, and the mixturewas stirred for 19 hr. The crystallized substance was collected byfiltration, washed with toluene (30 mL), and dried under reducedpressure at 60° C. to give the title compound. yellow powder, 3.86 g,yield 92.1%, purity 74.4%, optical purity 98.5% ee.

Conditions for High-Performance Liquid Chromatography Analysis (Purity)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.6 min (the title compound), 9.3 min (the raw material)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CHIRALPAK IA (manufactured by Daicel Chemical Industries),4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol for high-performance liquidchromatography/distilled water for high-performance liquidchromatography=80/15/5flow rate: 2.0 mL/minretention time: 10.2 min (R), 14.4 min (S)

¹H NMR (DMSO-d₆) δ 1.67 (d, J=6.6 Hz, 3H), 5.01 (brs, 1H), 8.58 (s, 1H),8.75 (brs, 3H), 8.80 (s, 1H), 8.90 (s, 1H), 11.88 (s, 1H).

Example 7 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

2-((1R)-1-((Benzhydrylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(1.00 g) and aluminium trichloride (0.516 g) were put into a Schlenkflask (50 mL). The atmosphere in the Schlenk flask was decompressed, andthe pressure was recovered with argon. The procedures were performedthree times in total. Dichloromethane (20 mL) and triethylsilane (0.924mL) were added thereto under argon atmosphere, and the reaction mixturewas stirred at 80° C. for 23 hr. The reaction mixture was cooled to roomtemperature, and the reaction was quenched with 30 wt % aqueous sodiumhydroxide solution (20 mL). The mixture was extracted three times withTHF. The obtained organic layers were combined, washed with brine, driedover sodium sulfate, and concentrated under reduced pressure to give apale yellow solid. This solid was suspended in acetonitrile (13.5 mL),and the suspension was heated to 50° C. (S)-Mandelic acid (0.294 g) wasadded thereto at 50° C., and the mixture was heated under reflux for 15min. The mixture was cooled to room temperature, and stirred at the sametemperature for 1.5 hr. The precipitate was collected by filtrationusing a glass filter, and the obtained white solid was washed withacetonitrile (3.5 mL), and dried at 50° C. for 2 hr under reducedpressure to give the title compound (0.655 g). yield 68%. HPLC areanormalization 100%. 99.3% de.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.4 mL/minretention time: 1.6 min. (the title compound); 5.5 min. (the rawmaterial)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 2.0 mL/mincolumn temperature: 40° C.retention time: 11.4 min. (R-form); 16.4 min. (S-form)

¹H NMR (DMSO-d₆) δ 1.40 (d, J=6.5 Hz, 3H), 4.26 (q, J=6.5 Hz, 1H), 4.72(s, 1H), 7.18-7.22 (m, 1H), 7.25-7.29 (m, 2H), 7.36-7.40 (m, 2H), 8.59(s, 1H), 8.72 (s, 1H), 8.77 (s, 1H).

Example 8 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamidehydrochloride

2-((1R)-1-((Benzhydrylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.80 g) was put into a Schlenk flask (50 mL). The atmosphere in theSchlenk flask was decompressed, and the pressure was recovered withargon. The procedures were performed three times in total.Dichloromethane (16 mL) was added thereto under argon atmosphere. Thissolution was cooled in an ice bath, and N-bromosuccinimide (0.414 g) wasadded thereto. The reaction mixture was stirred at 0° C. for 1 hr, andthen at room temperature for 2 hr, and the reaction was quenched with 15wt % aqueous sodium hydroxide solution (40 mL). The mixture wasextracted three times with dichloromethane. The obtained organic layerwas washed with brine, dried over sodium sulfate, and concentrated underreduced pressure to give a pale yellow solid. The solid was added toacetonitrile (6 mL), and the mixture was stirred at 0° C. for 30 min,and the resulting solid was collected by filtration to give thecorresponding imine (0.524 g, yield 66%). The imine was suspended inacetonitrile/water-20/1 (3.78 mL), and 1 mol/L hydrogen chloride-ethersolution (1.02 mL) was added thereto at room temperature. The mixturewas stirred at room temperature for hr, and filtered using Hirsch funnelto give a white solid. The solid was washed with acetonitrile (2 mL),and dried at 50° C. for 8 hr under reduced pressure to give the titlecompound (two step yield 63%). The remaining benzphenone (2%) in thecompound was confirmed by ¹H NMR analysis.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.4 mL/minretention time: 1.6 min. (the title compound); 2.3 min. (benzphenone);5.5 min. (the raw material)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 2.0 mL/mincolumn temperature: 40° C.retention time: 11.4 min. (R-form); 16.4 min. (S-form)

¹H NMR (DMSO-d₆) δ 1.65 (d, J=6.5 Hz, 3H), 4.92 (q, J=6.5 Hz, 1H), 8.58(s, 1H), 8.80 (s, 1H), 8.88 (s, 1H), 8.91 (br, 3H), 11.89 (s, 1H).

Examples 9-54 Synthesis of2-((1R)-1-((benzhydrylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

(E)-2-(1-(Benzhydrylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.0386 g), a catalyst (corresponding to s/c=20) and a ligand (1.1 or2.2 equivalent relative to the iridium catalyst) were put into a testtube. The test tube was set in an autoclave. The atmosphere in theautoclave was decompressed, and the pressure was recovered withnitrogen. The procedures were performed three times in total. Thepressure of the autoclave was recovered to normal pressure, and asolvent (0.75 mL) was added thereto. Hydrogen was fed into the autoclaveuntil the pressure was increased by 0.1 MPa, and the pressure wasrecovered to normal pressure. The procedures were performed ten times intotal. Hydrogen was fed into the autoclave until 3.0 MPa, and themixture was stirred at the internal temperature of 50° C. for 2 hr. Themixture was cooled to the internal temperature of about 20° C., and thehydrogen was released. The conversion and enantiomeric excess weremeasured by HPLC. The results are shown in Table 9.

The conversion can be calculated by the following formula.

Conversion=100×the desired compound/(the desired compound+the rawmaterial compound)

wherein the desired compound and raw material means each area inhigh-performance liquid chromatography.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.4 mL/minretention time: 5.5 min. (the title compound), 7.2 min. (the rawmaterial).

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 8.3 min. (S-form), 13.6 min. (R-form).

¹H NMR (CDCl₃) δ 1.56 (d, J=6.5 Hz, 3H), 2.19 (s, 1H), 4.05 (q, J=6.5Hz, 1H), 4.98 (s, 1H), 7.19-7.24 (m, 1H), 7.27-7.32 (m, 3H), 7.33-7.44(m, 6H), 8.26 (s, 1H), 8.41 (s, 1H), 8.44 (s, 1H), 8.69 (s, 1H).

TABLE 9 Ex. catalyst or metal source ligand solvent conversion (%) % eestereo  9 [Rh(cod)(R)-(S)-josiphos] OTf — THF 4.9 21.8 R 10[Rh(cod)(R)-(S)-josiphos] OTf — DCM 3.8 23.1 SR 11 Ir(cod)₂(BAr^(F) ₄)(R)-(S)-Josiphos MeOH 11.6 26.1 S 12 Ir(cod)₂(BAr^(F) ₄)(R)-(S)-Josiphos DCM 59.7 28.9 S 13 Ir(cod)₂(BAr^(F) ₄) (R)-BINAPToluene 27.939.1 39.1 S 14 Ir(cod)₂(BAr^(F) ₄) (R,R)-iPr-Duphos Toluene97.1 10.5 R 15 Ir(cod)₂(BAr^(F) ₄) (R)-(S)-Josiphos Toluene 69.4 38.8 S16 Ir(cod)₂(BAr^(F) ₄) (R)-Phanephos Toluene 79.3 52.5 R 17Ir(cod)₂(BAr^(F) ₄) (R)-xylyl-BINAP Toluene 47.2 62.9 S 18Ir(cod)₂(BAr^(F) ₄) (R,R)-DIPAMP Toluene 9.8 26.6 S 19 Ir(cod)₂(BAr^(F)₄) (R,R)-Quinox-P* Toluene 76.4 51.7 S 20 Pd(OCOCF₃)₂ (R)-BINAP MeOH10.0 11.7 S 21 Pd(OCOCF₃)₂ (R)-BINAP DCM 2.1 33.7 S 22 Pd(OCOCF₃)₂(R)-BINAP Toluene 1.6 28.1 S 23 RuCl₂{(R)-binap} — Toluene 6.0 21.0 R 24RuCl₂{(R)-binap}{R,R-dpen} — Toluene 17.2 100.0 S 25 (R,R)-Me-Duphos(R,R)-Me-Duphos Toluene 7.2 43.9 S 26 Ir(cod)₂(BAr^(F) ₄) (R,R)-Ph-BPEToluene 7.4 48.1 R 27 Ir(cod)₂(BAr^(F) ₄) (S,S)-Et-Ferrotne Toluene 4.033.4 R 28 Ir(cod)₂(BAr^(F) ₄) (S)-H8-BINAP Toluene 62.8 18.0 R 29Ir(cod)₂(BAr^(F) ₄) (S)-DTBM-Segphos Toluene 8.5 23.0 R 30Ir(cod)₂(BAr^(F) ₄) (R)-C3-Tunephos Toluene 15.4 26.2 S 31Ir(cod)₂(BAr^(F) ₄) (S)-MeO-BIPHEP Toluene 16.1 19.5 S 32Ir(cod)₂(BAr^(F) ₄) SL-W001-1 Toluene 12.1 40.1 R 33 Ir(cod)₂(BAr^(F) ₄)SL-J004-1 Toluene 43.3 11.1 S 34 Ir(cod)₂(BAr^(F) ₄) (S)-ShiP Toluene57.2 8.0 R 35 Ir(cod)₂(BAr^(F) ₄) (S)-MOP Toluene 28.8 51.9 S 36Ir(cod)₂(BAr^(F) ₄) (R)-QuINAP Toluene 0.8 46.0 R 37 Ir(cod)₂(BAr^(F) ₄)(R)-iPr-PHOX Toluene 6.3 0.9 R 38 Ir(cod)₂(BAr^(F) ₄) (S)-MonophosToluene 97.3 86.4 R 39 Ir(cod)₂(BAr^(F) ₄) (S)-Me-Monophos Toluene 7.433.3 R 40 Ir(cod)₂(BArF₄) (R,R)-Taddol-type Toluene 30.3 16.2 R 41Ir(cod)₂(BAr^(F) ₄) (S)-BnMe Toluene 22.6 57.5 R 42 Ir(cod)₂(BAr^(F) ₄)(S,R,R)-alpha- Toluene 2.9 37.1 R phenethyl 43 Ir(cod)₂(BAr^(F) ₄)(S)-Et-Monophos Toluene 4.1 56.2 R 44 Ir(cod)₂(BAr^(F) ₄) (S)-MorphosToluene 52.6 92.9 R 45 Ir(cod)₂(BAr^(F) ₄) (S)-alpha-phenethylH Toluene1.7 27.1 R 46 Ir(cod)₂(BAr^(F) ₄) (S)-Pipphos Toluene 98.1 62.5 R 47Ir(cod)₂(BAr^(F) ₄) (S)-H8-Monophos Toluene 20.2 12.4 R 48 [Ir(cod)₂]BF₄(S)-Monophos DCM 15.6 70.9 R 49 [Ir(cod)₂]BF₄ (S)-Morphos DCM 3.3 43.5 R50 [Ir(cod)₂]BF₄ (S)-Pipphos DCM 5.8 62.0 R 51 [Ir(cod)₂]BF₄(R)-Phanephos DCM 82.7 47.1 R 52 Ir(cod)₂(BAr^(F) ₄) (S)-Monophos DCM98.7 89.4 R 53 Ir(cod)₂(BAr^(F) ₄) (S)-Morphos DCM 89.6 92.6 R 54Ir(cod)₂(BAr^(F) ₄) (S)-Pipphos DCM 72.2 83.4 R

Reference Example 3 Synthesis of(E)-2-(1-(bis(4-methoxyphenyl)methyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(13.00 g), 4,4′-dimethoxybenzhydrylamine (10.00 g), ethanol (65 mL) andacetic acid (0.642 mL) were put into a four-necked eggplant flask (200mL), and the mixture was stirred for 8 hr with heating under refluxunder nitrogen atmosphere. The reaction mixture was cooled to roomtemperature, ethanol (10 mL) was added thereto, and the mixture wasfiltered. The residual white solid was washed with ethanol (30 mL), andthe filtrate and washing were combined, and concentrated under reducedpressure to give a solid. To the solid was added toluene (80 mL), andthe mixture was heated to 99° C. Hexane (190 mL) was added dropwisethereto at 73 to 99° C., and the mixture was stirred at 73° C. (refluxtemperature) for 10 min, and cooled to room temperature. The resultingcrystals were aged at room temperature. The crystals were collected byfiltration, washed with a mixed solvent (60 mL) of hexane and toluene(1:3), and dried under reduced pressure at 60° C. to give the titlecompound (16.57 g, yield 77%) as a pale-brown solid.

¹H NMR (CDCl₃) δ 2.45 (s, 3H), 3.78 (s, 6H), 5.82 (s, 1H), 6.86 (d,J=9.0 Hz, 4H), 7.33 (d, J=9.0 Hz, 4H), 8.36 (s, 1H), 8.44 (s, 1H), 8.57(bs, 1H), 8.69 (s, 1H); ¹³C NMR (CDCl₃) δ 14.62, 55.26, 67.42, 111.89(q, J=5.4H z), 114.01, 121.45 (q, J=275.2 Hz), 124.06, 128.30, 135.16,135.91, 137.81 (q, J=32.7 Hz), 145.41, 149.48, 149.92, 158.68, 158.81,159.67, 176.60.

Reference Example 4 Synthesis of(E)-2-(1-(2-benzoylhydrazono)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(1.00 g), benzoylhydrazine (0.408 g) and p-toluenesulfonic acidmonohydrate (0.0272 g) were put into a four-necked eggplant flask (50mL). Methanol (15 mL) was added thereto under nitrogen atmosphere, andthe mixture was stirred at 60° C. for 1 hr. The reaction mixture wascooled in a water bath, and the precipitate was collected by filtrationusing a glass filter. The resulting white solid was washed with methanol(5 mL), and dried under reduced pressure at 50° C. to give the titlecompound (1.21 g). yield 91%, HPLC area normalization 99.3%. E/Z isomerratio 11/1.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 1.47 min. (benzoylhydrazine), 4.36 min. (the titlecompound), 4.48 min. (the raw material)

¹H NMR (DMSO-d₆) δ 2.48 (s, 3H), 7.50-7.57 (m, 2H), 7.58-7.65 (m, 1H),7.81-7.94 (m, 2H), 8.59 (s, 1H), 8.78 (s, 1H), 8.86 (s, 1H), 11.22 (bs,1H), 11.81 (bs, 1H).

Reference Example 5 Synthesis of (E)-(S)-tert-butyl2-(1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethylidene)hydrazinecarboxylate

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(6.00 g) was put into a four-necked eggplant flask (100 mL). Theatmosphere in the container was decompressed, and the pressure wasrecovered with nitrogen. The procedures were performed three times intotal. Toluene (18 mL), acetic acid (3.6 mL) andtert-butoxycarbonylhydrazine (0.408 g) were added thereto under nitrogenatmosphere, and the mixture was stirred at 60° C. for 2 hr. The reactionmixture was cooled in a water bath, and thereby the objective productwas precipitated. The mixture was aged at room temperature, and then for1 hr, and the precipitate was collected by filtration using a glassfilter. The resulting white solid was washed with toluene/hexane=1/1 (50mL), and dried under reduced pressure at 50° C. to give the titlecompound (7.18 g). yield 89%, HPLC area normalization 93.9%.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 4.48 min. (the raw material); 5.66 min. (the titlecompound)

¹H NMR (DMSO-d₆) δ 1.51 (s, 9H), 2.31 (s, 3H), 8.58 (s, 1H), 8.75 (s,1H), 8.80 (s, 1H), 10.46 (s, 1H), 11.74 (s, 1H); ¹³C NMR (DMSO-d₆) δ12.59, 27.95, 80.33, 111.81 (q, J=5.4 Hz), 121.58 (q, J=274.3 Hz),121.62, 134.85, 135.32 (q, J=31.8 Hz), 145.51, 149.70, 151.33, 152.23,159.69, 172.44; ¹⁹F NMR (DMSO-d₆) δ −63.81.

Reference Example 6 Synthesis of(E)-2-(1-(benzylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(6.00 g) was put into a four-necked eggplant flask (100 mL). Toluene (30mL), benzyl alcohol (1.97 mL) and acetic acid (0.196 mL) were addedthereto under nitrogen atmosphere, and the mixture was stirred at 90° C.for 2 hr. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure. The crude objective product wassuspended in hexane/ethyl acetate=9/1 (60 mL), and the suspension wasdissolved with heating at 90° C., and the solution was cooled to 0° C.to precipitate crystals. The mixture was aged at 0° C. for 30 min, andthe precipitate was collected by filtration using a glass filter. Theresulting pale-orange solid was washed with hexane/ethyl acetate=9/1 (30mL), and dried under reduced pressure at 50° C. to give the titlecompound (6.83 g). yield 91%, HPLC area normalization 84.7%.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 4.48 min. (the raw material), 16.4 min. (the titlecompound)

Reference Example 7 Synthesis of(E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)imino)ethyl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(6.00 g) was put into a four-necked eggplant flask (100 mL). Toluene (30mL), 4-methoxybenzylamine (2.35 mL) and acetic acid (0.196 mL) wereadded thereto under nitrogen atmosphere, and the mixture was stirred at85° C. for 2 hr. The reaction mixture was cooled to room temperature,and concentrated under reduced pressure. The crude objective product wassuspended in ethanol (48 mL), and the suspension was dissolved withheating at 70° C., and the solution was cooled to room temperature toprecipitate crystals. The precipitate was collected by filtration usinga glass filter, washed with ethanol (20 mL), and dried under reducedpressure at 60° C. to give the title compound (5.64 g) as a singleisomer. pale-orange solid, yield 70%, HPLC area normalization 99.4%.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 4.7 min (the raw material); 11.2 min. (the titlecompound).

¹H NMR (CDCl₃) δ 2.47 (s. 3H), 3.82 (s, 3H), 4.74 (s, 2H), 6.92 (d,J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 8.37 (s, 1H), 8.40 (s, 1H), 8.44(s, 1H), 8.67 (s, 1H).

Synthesis of Reference Example 8(E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)imino)ethyl)-1,3-thiazole-5-carboxamide

The title compound (6.81 g) was obtained as a single isomer in the samemanner as in Reference Example 7. yellow solid, yield 75%, HPLC areanormalization 96.2%.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 4.7 min (the raw material); 12.1 min. (the titlecompound).

¹H NMR (CDCl₃) δ 2.47 (s. 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.70 (s, 2H),6.49 (d, J=2.5 Hz, 1H), 6.52 (dd, J=8.5, 2.5 Hz, 1H), 7.36 (d, J=8.5 Hz,1H), 8.37 (s, 1H), 8.41 (s, 1H), 8.43 (s, 1H), 8.68 (s, 1H).

Reference Example 9 Synthesis of(E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxyphenyl)imino)ethyl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(1.00 g), p-toluenesulfonic acid monohydrate (0.0272 g) and p-anisidine(0.369 g) were put into a four-necked eggplant flask (50 mL). Toluene (6mL) was added thereto under nitrogen atmosphere, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was cooled to roomtemperature, and concentrated under reduced pressure. The crudeobjective product was suspended in ethanol (10 mL), and the suspensionwas dissolved with heating at 65° C. Water (10 mL) was added dropwisethereto at the same temperature, and the mixture was cooled to roomtemperature. The obtained red-brown suspension was stirred at roomtemperature for 30 min, and the precipitate was collected by filtrationusing a glass filter, washed with ethanol/water=1/1 (10 mL), and driedunder reduced pressure at 50° C. to give the title compound (1.08 g) asa single isomer. brown solid, yield 83%, HPLC area normalization 91.7%.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 4.7 min. (the raw material); 28.0 min. (the titlecompound).

¹H NMR (DMSO-d₆) δ 2.37 (s. 3H), 3.78 (s, 3H), 6.86-7.05 (m, 4H), 8.59(s, 1H), 8.78 (s, 1H), 8.93 (s, 1H), 11.85 (s, 1H); ¹³C NMR δ 16.18,55.22, 111.89, 114.19, 122.08 (q, J=274.28 Hz), 121.79, 122.00, 135.36(q, J=32.7 Hz), 136.93, 141.46, 146.01, 149.74, 151.27, 156.78, 159.61,160.61, 174.22; ¹⁹F NMR δ−63.81.

Example 55 Synthesis of2-((1R)-1-((bis(4-methoxyphenyl)methyl)amino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

(E)-2-(1-((Bis(4-methoxyphenyl)methyl)imino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(3.00 g), [Ir(cod)₂]BARF (0.0664 g) and (S)-MONOPHOS (0.0412 g) were putinto an autoclave (120 mL). The atmosphere in the autoclave wasdecompressed, and the pressure was recovered with argon. The procedureswere performed five times in total. The pressure of the autoclave wasrecovered to normal pressure, and dehydrated dichloromethane (30 mL) fororganic synthesis was fed thereto by argon pressure. Hydrogen was fedinto the autoclave until the pressure was increased by 0.1 MPa, and thepressure was recovered to normal pressure. The procedures were performedten times in total. Hydrogen was fed into the autoclave until 1.0 MPa,and the mixture was stirred at the internal temperature of 50° C. for 24hr. The mixture was cooled to the internal temperature of about 20° C.,the hydrogen was released, and the atmosphere was replaced with argon(conversion 73.7%, optical purity 93.7% ee). The reaction solution wasconcentrated under reduced pressure, and the residue was purified bysilica gel column to give the title compound. pale-brown solid, 1.54 g,yield 50%, HPLC area normalization 96.2%.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.4 min (the title compound)

¹H NMR (CDCl₃) δ 1.54 (d, J=6.6 Hz, 3H), 4.42 (q, J=6.6 Hz, 1H), 7.23(d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H). ¹³C NMR (CDCl₃) δ 24.66,49.65, 118.36, 142.38, 178.38.

Example 56 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamidehydrochloride

2-((1R)-1-((Bis(4-methoxyphenyl)methyl)amino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.150 g) was dissolved in a mixed solvent of acetonitrile and water(9:1, 3.0 mL), and to this solution was added dropwise 1 mol/L hydrogenchloride-diethyl ether solution (0.312 mL). The mixture was warmed to50° C., and the mixture was stirred overnight at the same temperature.The mixture was cooled to room temperature, and the resulting crystalswere collected by filtration to give the title compound. colorlesssolid, 0.0776 g, yield 77%.

Examples 57-101 Synthesis of2-((1R)-1-(2-benzoylhydrazinyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

(E)-2-(1-(2-Benzoylhydrazono)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.0702 g), a catalyst (corresponding to s/c=20), a ligand (1.1 or 2equivalent relative to the catalyst) and an additive (potassium butoxidewas used in an amount of 1 equivalent relative to the substrate inExamples 57-62, and the additive was not used in Examples 63-101) wereput into a test tube. A solvent (1 mL) was added thereto under nitrogenatmosphere, the test tube was set in an autoclave, and the reactionsystem was purged with hydrogen. Hydrogen was fed into the autoclaveuntil 5.0 MPa, and the mixture was stirred at 50° C. for 16 hr. Theproduction of the title compound was confirmed by analyzing the reactionsolution using HPLC. The results are shown in Table 10.

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=1/1flow rate: 1.0 mL/minretention time: 5.4 min. (S-form); 6.1 min. (R-form); 7.6 min. (the rawmaterial)

TABLE 10 Ex. catalyst or metal source ligand solvent conversion (%) % eestereo  57 RuCl₂{(R)-binap}{R,R-dpen} — IPA 25.9 75.1 S  58RuCl₂{(R)-binap}{R,R-dach} — IPA 51.4 71.2 S  59RuCl₂{(R)-binap}{R,R-daipen} — IPA 41.5 85.3 S  60RuCl₂{(R)-xyl-binap}{R,R-dpen} — IPA 30.5 40.5 S  61RuCl₂{(R)-xyl-binap}{R,R-dach} — IPA 28.9 38.3 R  62RuCl₂{(R)-xyl-binap}{R,R-daipen} — IPA 28.0 62.6 S  63 [IrCl(cod)]₂(R,R)-iPr-Duphos DCM 9.8 7.2 R  64 [RhCl(cod)]₂ (R,R)-iPr-Duphos MeOH77.0 69.1 R  65 [RhCl(cod)]₂ (R)-(S)-Josiphos MeOH 98.5 17.1 S  66[RhCl(cod)]₂ (R)-Phanephos MeOH 99.3 43.9 R  67 [RhCl(cod)]₂(R,R)-Quinox-P* MeOH 24.5 13.9 R  68 [Rh(cod)₂]OTf (R)-BINAP MeOH 19.831.1 S  69 [Rh(cod)₂]OTf (R,R)-iPr-Duphos MeOH 89.9 70.2 R  70[Rh(cod)₂]OTf (R)-Phanephos MeOH 98.8 45.4 R  71[Rh(cod)(S)-skewphos]OTf — MeOH 57.1 68.1 S  72[Rh(nbd)(R)-(S)-josiphos]BF₄ — MeOH 58.9 16.4 S  73[Rh(nbd)(S,S)-bisP*]BF₄ — MeOH 45.0 61.4 S  74 [Rh(cod)₂]OTf(R,R)-iPr-Duphos MeOH 14.6 68.2 S  75 [Rh(cod){(R,R)-Et-duphos}]OTf —MeOH 31.4 79.8 S  76 [Rh(cod)₂]OTf (R,R)-Ph-BPE MeOH 23.0 50.3 R  77[Rh(cod)₂]OTf (R,R)-cataciumM(R) MeOH 27.3 54.8 S  78 [Rh(cod)₂]OTf(S,S)-Et-Ferrotne MeOH 99.4 26.4 S  79 [Rh(cod){(S,S)-ptbp-skewphos}]OTf— MeOH 48.4 70.5 S  80 [Rh(cod)₂]OTf (R,R)-Norphos MeOH 29.3 72.4 S  81[Rh(cod)₂]OTf (S)-xyl-Phanephos MeOH 98.5 50.9 S  82 [Rh(cod)₂]OTfcataASium T3 MeOH 25.1 47.0 R  83 [Rh(cod)₂]OTf SL-J004-1 MeOH 57.6 25.1R  84 [Rh(cod)₂]OTf (S)(R)-SL-J002-02 MeOH 99.2 81.9 S  85 [Rh(cod)₂]OTf(R)(S)-SL-J502-1 MeOH 98.7 58.5 R  86 [Rh(cod)₂]OTf (R)(S)-SL-J009-1MeOH 99.6 16.0 R  87 [Rh(cod)₂]OTf (R)(S)-SL-J005-1 MeOH 38.6 8.6 R  88[Rh(cod)₂]OTf (R)(S)-SL-J011-1 MeOH 99.2 90.7 R  89 [Rh(cod)₂]OTf(R)(S)-SL-J013-1 MeOH 98.7 86.0 R  90 [Rh(cod)₂]OTf (R)(S)-SL-J212-1MeOH 99.2 67.1 R  91 [Rh(cod)₂]OTf (R)(S)-SL-J216-1 MeOH 24.5 49.5 R  92[Rh(cod)₂]OTf (R)(S)-SL-J014-1 MeOH 98.8 87.8 R  93 [Rh(cod)₂]OTf(R)(S)-SL-J202-1 MeOH 99.2 82.7 R  94 [Rh(cod)₂]OTf (R)(S)-SL-J203-2MeOH 99.6 67.6 S  95 [Rh(cod)₂]OTf (R)(S)-SL-J210-1 MeOH 98.9 91.8 R  96[Rh(cod)₂]OTf SL-M001-1 MeOH 65.4 6.0 R  97 [Rh(cod)₂]OTf SL-W001-1 MeOH98.5 37.0 R  98 [Rh(cod)₂]OTf SL-W002-1 MeOH 81.9 47.0 R  99[Rh(cod)₂]OTf SL-W003-1 MeOH 99.4 22.6 R 100 [Rh(cod)₂]OTf SL-T001-1MeOH 97.0 72.2 S 101 [Rh(cod)₂]OTf SL-T002-1 MeOH 23.2 62.9 S

Example 102 Synthesis of2-((1S)-1-(2-benzoylhydrazinyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[Rh(cod)₂]OTf (0.0020 g) and (S) (R)-SL-J210-2 (0.0037 g) were put intoa Schlenk flask (20 mL). The atmosphere in the container wasdecompressed, and the pressure was recovered with argon. The procedureswere performed five times in total. The pressure of the container wasrecovered to normal pressure, dehydrated methanol (20 mL) for organicsynthesis was added thereto, and the mixture was stirred at roomtemperature for 1 hr. Separately,(E)-2-(1-(2-benzoylhydrazono)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(2.00 g) was put into an autoclave. The atmosphere in the container wasdecompressed, and the pressure was recovered with argon. The procedureswere performed seven times in total. The pressure of the container wasrecovered to normal pressure, and the rhodium catalyst methanolsolution, which was prepared above, was fed thereto by argon pressure.The Schlenk container was washed with methanol (20 mL), and the washingwas added by argon pressure. Hydrogen was fed into the container until1.0 MPa, and the mixture was stirred at the internal temperature of 50°C. for 20 hr. The mixture was cooled to the internal temperature ofabout 20° C., and the hydrogen was released. The production of the titlecompound was confirmed by analyzing the reaction solution using HPLC(conversion 99% or more, 90% ee). The reaction mixture was concentratedto give a yellow solid. The solid was suspended in acetonitrile (4mL)/diisopropyl ether (16 mL), and the suspension was stirred at 60° C.for 1 hr, cooled to room temperature and stirred overnight. Theprecipitate was collected by filtration using a glass filter, and washedwith acetonitrile (2 mL)/diisopropyl ether (8 mL). The obtained solidwas dried under reduced pressure at 60° C. to give the title compound(yield-86%, 91% ee). HPLC area normalization 98.3%.

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=1/1flow rate: 1.0 mL/minretention time: 5.4 min. (S-form); 6.1 min. (R-form); 7.6 min. (the rawmaterial)

¹H NMR (CDCl₃) δ 1.62 (d, J=6.5 Hz, 3H), 4.64 (qd, J=6.5, 2.0 Hz, 1H),5.31 (dd, 1H), 7.43 (t, J=7.5 Hz, 2H), 7.53 (tt, J=8.0, 1.5 Hz, 1H),7.71 (dd, J=8.0, 1.5 Hz, 2H), 7.84 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 8.43(s, 1H), 8.67 (s, 2H); ¹⁹F NMR (CDCl₃) δ −64.77; ¹³C NMR (CDCl₃) δ20.43, 59.12, 111.96 (q, J=5.4 Hz), 121.4 (q, J=275.2 Hz), 123.97,126.96, 128.78, 132.16, 132.37, 133.55, 137.79 (q, J=33.6 Hz), 144.67,149.42, 150.04, 158.94, 168.02, 180.68.

Example 103 Synthesis of2-((1S)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamidehydrochloride

2-((1S)-1-(2-Benzoylhydrazinyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.0500 g) and zinc powder (0.0152 g) were put into a Schlenk flask (10mL). The atmosphere in the container was decompressed, and the pressurewas recovered with argon. The procedures were performed three times intotal. Methanol (2.0 mL) and chlorotrimethylsilane (0.002 mL) were addedthereto at room temperature. After confirming that the reaction solutionbecame gray, benzoic acid (0.029 g) was added thereto, and the reactionmixture was stirred at room temperature for 17 hr. The production of thetitle compound was confirmed by HPLC (55.8% ee)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-H (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 270 nmmobile phase: hexane for high-performance liquidchromatography/isopropyl alcohol/methanol/diethylamine-80/15/5/0.1flow rate: 1.0 mL/minretention time: 5.7 min. (S-form); 8.6 min. (R-form)

Examples 104-111 Synthesis of tert-butyl2-((1S)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethyl)hydrazinecarboxylate

tert-Butyl2-(1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazol-2-yl)ethylidene)hydrazinecarboxylate(0.0696 g), a catalyst (corresponding to s/c=20) and a ligand (1.1equivalent relative to the catalyst) were put into a test tube. Asolvent (1.5 mL) was added thereto under nitrogen atmosphere, the testtube was set in an autoclave, and the reaction system was purged withhydrogen. Hydrogen was fed into the autoclave until 1.0 MPa, and themixture was stirred at 50° C. for 15 hr. The production of the titlecompound was confirmed by analyzing the reaction solution using HPLC.The results are shown in Table 11.

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=1/1flow rate: 0.5 mL/minretention time: 12.8 min. (enantiomer-A); 14.6 min. (the raw material);16.1 min. (enantiomer-B)

TABLE 11 catalyst or Ex. metal source ligand solvent conversion (%) % ee104 [Rh(cod)₂]OTf (S,S)-Et-Ferrotne IPA 77.2 61.0 105 [Rh(cod)₂]OTf(R,R)-iPr-Duphos IPA 20.7 −66.3 106 [Rh(cod)₂]OTf (S)-xyl-Phanephos IPA78.5 94.9 107 [Rh(cod)₂]OTf SL-T001-1 IPA 27.2 46.7 108 [Rh(cod)₂]OTf(S) (R)-SL-J002-02 IPA 98.9 11.0 109 [Rh(cod)₂]OTf (R) (S)-SL-J011-1 IPA97.5 37.2 110 [Rh(cod)₂]OTf (R) (S)-SL-J014-1 DCM 98.9 3.3 111[RhC1(cod)]₂ (R) (S)-SL-J210-2 MeOH 85.5 −24.6

Examples 112-149 Synthesis of2-(1-(benzylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

(E)-2-(1-(Benzylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.0658 g), a catalyst (corresponding to s/c=20), a ligand (1.1 or 2equivalent relative to the catalyst) and an additive (potassium butoxidewas used in an amount of 1 equivalent relative to the substrate inExamples 113-118, and the additive was not used in Examples 119-149)were put into a test tube. A solvent (1 mL) was added thereto undernitrogen atmosphere, the test tube was set in an autoclave, and thereaction system was purged with hydrogen. Hydrogen was fed into theautoclave until 5.0 MPa, and the mixture was stirred at 50° C. for 20hr. The production of the title compound was confirmed by analyzing thereaction solution using HPLC. The results are shown in Table 12.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.4 mL/minretention time: 7.2 min. (the title compound); 12.0 min. (the rawmaterial).

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 4.8 min. (the title compound); 7.2 min. (the rawmaterial); 11.9 min. (the title compound)

TABLE 12 Ex. catalyst ormetal source ligand solvent conversion (%) % ee112 RuCl₂{(R)-binap} — IPA 47.9 −6.2 113 RuCl₂{(R)-binap}{R,R-dpen} —IPA 20.7 −8.8 114 RuCl₂{(R)-binap}{R,R-dach} — IPA 22.7 2.9 115RuCl₂{(R)-binap}{R,R-daipen} — IPA .35.9  8.1 116RuCl₂{(R)-xyl-binap}{R,R-dpen} — IPA 23.1 −9.0 117RuCl₂{(R)-xyl-binap}{R,R-dach} — IPA  8.8 17.6 118RuCl₂{(R)-xyl-binap}{R,R-daipen} — IPA 19.7 −14.9 119 [IrCl(cod)]₂(R)-BINAP Toluene 55.7 4.0 120 [IrCl(cod)]₂ (R,R)-iPr-Duphos Toluene57.5 1.4 121 [IrCl(cod)]₂ (R,R)-Skewphos Toluene 28.7 3.6 122[IrCl(cod)]₂ (R)-(S)-Josiphos Toluene 59.7 6.8 123 [IrCl(cod)]₂(R)-Phanephos Toluene 65.0 4.0 124 [IrCl(cod)]₂ (R)-iPr-PHOX Toluene61.5 2.2 125 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos Toluene 42.8 22.2 126Ir(cod)₂(BAr₄ ^(F)) (R)-Phanephos Toluene 23.5 −6.6 127Ir(cod){(S,S)-Ph₂PThrePHOX} (BAr₄ ^(F)) — Toluene  5.0 33.1 128Ir(cod){(S,S)-Cy₂PThrePHOX} (BAr₄ ^(F)) — Toluene 26.7 2.0 129[RhCl(cod)]₂ (R)-BINAP MeOH 21.9 10.1 130 [RhCl(cod)]₂ (R,R)-iPr-DuphosMeOH 39.5 7.3 131 [RhCl(cod)]₂ (R,R)-Skewphos MeOH 78.8 3.5 132[RhCl(cod)]₂ (R)-(S)-Josiphos MeOH 75.8 −0.1 133 [RhCl(cod)]₂(R)-Phanephos MeOH 62.1 −9.0 134 [RhCl(cod)]₂ (R,R)-DIPAMP MeOH 66.9 5.4135 [RhCl(cod)]₂ (R,R)-Quinox-P* MeOH 89.9 12.1 136 [Rh(cod)₂]OTf(R)-BINAP MeOH 36.0 7.3 137 [Rh(cod)₂]OTf (R,R)-iPr-Duphos MeOH 71.4 2.6138 [Rh(cod)₂]OTf (R)-Phanephos MeOH 60.0 −10.2 139 [Rh(cod)(S)-skewphos]OTf — MeOH 87.8 3.3 140 [Rh(nbd) (R)-(S)-josiphos]BF₄ —MeOH 93.9 2.4 141 [Rh(nbd) (S,S)-bisP*]BF₄ — MeOH 92.1 2.1 142 [Rh(cod)(R,R)-dipamp]BF₄ — MeOH 68.0 3.3 143 [Rh(cod) (S)-xyl-binap]OTf — MeOH77.1 2.9 144 [IrCl(cod)]₂ (R)-(S)-Josiphos DCM 99.4 3.7 145 [IrCl(cod)]₂(R)-iPr-PHOX DCM 98.9 3.2 146 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos DCM34.9 9.5 147 Ir(cod)₂(BAr₄ ^(F)) (R)-iPr-PHOX MeOH 30.7 −5.6 148Ir(cod)₂(BAr₄ ^(F)) (R)-iPr-PHOX DCM 51.2 2.6 149 Ir(cod)₂(BAr₄ ^(F))(S)-Monophos Toluene 57.6 −78.8

Examples 150-156 Synthesis ofN-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)amino)ethyl)-1,3-thiazole-5-carboxamide

N-(5-Chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)imino)ethyl)-1,3-thiazole-5-carboxamide(0.0351 g), a catalyst (corresponding to s/c=20) and a ligand (1.1 or 2equivalent relative to the catalyst) were put into a test tube. Asolvent (0.75 mL) was added thereto under nitrogen atmosphere, the testtube was set in an autoclave, and the reaction system was purged withhydrogen. Hydrogen was fed into the autoclave until 3.0 MPa, and themixture was stirred at 50° C. for 2 hr. The production of the titlecompound was confirmed by analyzing the reaction solution using HPLC.The results are shown in Table 13.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 6.9 min. (the title compound); 11.2 min. (the rawmaterial).

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 5.0 min. (the title compound); 6.0 min. (the titlecompound); 7.4 min. (the raw material)

TABLE 13 catalyst or conver- Ex. metal source ligand solvent sion (%) %ee 150 [Rh(cod) — MeOH 14.0 −9.7 (R)-(S)-josiphos]OTf 151 [Rh(cod) — THF5.4 −22.1 (R)-(S)-josiphos]OTf 152 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-JosiphosMeOH 31.4 17.2 153 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos THF 26.8 24.4154 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos DCM 99.4 17.1 155 Ir(cod)₂(BAr₄^(F)) (R)-(S)-Josiphos Toluene 65.2 21.6 156 Ir(cod)₂(BAr₄ ^(F))(S)-Monophos Toluene 74.6 −74.0

Examples 157-162 Synthesis ofN-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)amino)ethyl)-1,3-thiazole-5-carboxamide

N-(5-Chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)imino)ethyl)-1,3-thiazole-5-carboxamide(0.0351 g), a catalyst (corresponding to s/c=20) and a ligand (1.1 or 2equivalent relative to the catalyst) were put into a test tube. Asolvent (0.75 mL) was added thereto under nitrogen atmosphere, the testtube was set in an autoclave, and the reaction system was purged withhydrogen. Hydrogen was fed into the autoclave until 3.0 MPa, and themixture was stirred at 50° C. for 2 hr. The production of the titlecompound was confirmed by analyzing the reaction solution using HPLC.The results are shown in Table 15.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCArea Normalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 6.3 min. (the title compound); 12.1 min. (the rawmaterial).

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150 mmUV detection wavelength: 254 nm

TABLE 14 mobile phase: acetonitrile for high- 0.025 mol/L performanceliquid aqueous potassium chromatography dihydrogenphosphate solution 0.0-10.0 min. 40% 60% 10.1-20.0 min. 80% 20%acetonitrile for high-performance liquid chromatography/0.025 mol/Laqueous potassium dihydrogenphosphate solution=4/6, 10 minflow rate: 1.2 mL/minretention time: 6.0 min. (the title compound); 6.5 min. (the titlecompound); 10.8 min. (the raw material)

TABLE 15 catalyst or conversion Ex. metal source ligand solvent (%) % ee157 [Rh(cod) — THF 1.3 −10.5 (R)-(S)-josiphos]OTf 158 [Rh(cod) — DOM 4.4— (R)-(S)-josiphos]OTf 159 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos THF 24.117.5 160 Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos DCM 68.6 11.5 161Ir(cod)₂(BAr₄ ^(F)) (R)-(S)-Josiphos Toluene 93.1 18.5 162 Ir(cod)₂(BAr₄^(F)) (S)-Monophos Toluene 45.6 −80.0

Reference Example 10 Synthesis of(E)-1,1-diphenyl-N-(1-phenylethylidene)methanamine

Acetophenone (4.92 g), toluene (50 mL), benzhydrylamine (7.88 g) andacetic acid (0.5 mL) were put into a four-necked eggplant flask (100 mL)equipped with Dean-Stark trap, and the mixture was stirred at theexternal temperature of 135° C. for 6 hr. The reaction mixture wascooled to room temperature, and concentrated under reduced pressure togive an oil. To the oil was added normal hexane, and the mixture wasstirred at 0° C. for 2 hr. The resulting solid was collected byfiltration, washed with normal hexane (20 mL), and dried under reducedpressure at 50° C. to give the title compound (4.13 g, yield 35%) as awhite solid.

¹H NMR (CDCl₃) δ 2.26 (s, 3H), 5.84 (s, 1H), 7.12-7.21 (m, 2H),7.24-7.30 (m, 4H), 7.33-7.39 (m, 3H), 7.42-7.50 (m, 4H), 7.88-7.96 (m,2H); ¹³C NMR (CDCl₃) δ 16.03, 68.52, 126.81, 127.08, 127.70, 128.25,128.52, 129.73, 141.33, 144.97, 164.51.

Reference Example 11 Synthesis of(E)-N-(1-(4-methoxyphenyl)ethylidene)-1,1-diphenylmethanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (30 mL), 4′-methoxyacetophenone (5.00 g),benzhydrylamine (6.03 mL) and acetic acid (0.38 mL) were added thereto,and the mixture was stirred for at the internal temperature of 90° C.for 22 hr. The reaction mixture was cooled to room temperature, andfiltered using Hirsch funnel, and the filtrate was concentrated underreduced pressure to give an oil. To the oil was added normal hexane (30mL), and the oil was dissolved at 90° C. The mixture was cooled to roomtemperature, and stirred for 1 hr. The resulting solid was collected byfiltration, washed with normal hexane (20 mL), and dried under reducedpressure at 40° C. The obtained white solid (5.55 g) was again dissolvedwith heating in normal hexane (20 mL) at 90° C., and the solution wascooled to room temperature, and stirred overnight at room temperature.The resulting solid was collected by filtration, washed with normalhexane (10 mL), and dried under reduced pressure at 40° C. to give thetitle compound (4.81 g, yield 46%) as a white solid.

¹H NMR (CDCl₃) δ 2.27 (s, 3H), 3.82 (s, 3H), 5.83 (s, 1H), 6.90 (d,J=9.0 Hz, 2H), 7.19 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 4H), 7.46 (d,J=7.5 Hz, 4H), 7.92 (d, J=9.0 Hz, 2H);

¹³C NMR (CDCl₃) δ 15.60, 55.31, 68.23, 113.40, 126.60, 127.56, 128.35,128.44, 133.98, 145.08, 160.92, 163.47.

Reference Example 12 Synthesis of(E)-N-(1-(4-chlorophenyl)ethylidene)-1,1-diphenylmethanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (30 mL), 4′-chloroacetophenone (5.00 mL),benzhydrylamine (7.97 mL) and acetic acid (0.44 mL) were added thereto,and the mixture was stirred at the internal temperature of 100° C. for25 hr. 7 hr after the beginning of the stirring, additionalbenzhydrylamine (1.3 mL) was added thereto. The reaction mixture wascooled to room temperature, and filtered using Hirsch funnel, and thefiltrate was concentrated under reduced pressure to give a white solid.To the solid was added normal hexane (50 mL), and the mixture was heatedunder reflux for 20 min, cooled to 0° C., and stirred at the sametemperature for 1 hr. The resulting solid was collected by filtration,washed with normal hexane (30 mL) cooled to 0° C., and dried underreduced pressure at 40° C. to give the title compound (8.25 g, yield67%) as a white solid.

¹H NMR (CDCl₃) δ 2.29 (s, 3H), 5.85 (s, 1H), 7.20 (t, J=7.5 Hz, 2H),7.30 (t, J=7.5 Hz, 4H), 7.35 (d, J=8.5 Hz, 2H), 7.44 (d, J=7.5 Hz, 4H),7.88 (d, J=8.5 Hz); ¹³C NMR (CDCl₃) δ15.75, 68.50, 126.79, 127.51,128.31, 128.45, 135.75, 139.52, 144.64, 163.16 (two peaks are duplicatedin one of the underlined peaks).

Reference Example 13 Synthesis of(E)-1,1-diphenyl-N-(1-(4-trifluoromethylphenyl)ethylidene)methanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (30 mL), 4′-trifluoromethylacetophenone (5.00g), benzhydrylamine (5.72 mL) and acetic acid (0.31 mL) were addedthereto, and the mixture was stirred at the internal temperature of 100°C. for 16 hr. The reaction mixture was cooled to room temperature, andfiltered using Hirsch funnel, and the filtrate was concentrated underreduced pressure to give a white solid. To the solid was added normalhexane (30 mL), and the mixture was stirred at 90° C., cooled to 0° C.,and stirred at the same temperature for 1 hr. The resulting solid wascollected by filtration, washed with normal hexane (20 mL) cooled to 0°C., and dried under reduced pressure at 40° C. to give the titlecompound (4.68 g, yield 50%) as a white solid. The residual filtrate wasconcentrated under reduced pressure, and the residue was recrystallizedfrom normal hexane (15 mL) at −20° C. to give the title compound (1.45g, yield 15%) as a white solid.

¹H NMR (CDCl₃) δ 2.33 (s, 3H), 5.88 (s, 1H), 7.21 (t, J=7.5 Hz, 2H),7.31 (d, J=7.5 Hz, 4H), 7.45 (d, J=7.5 Hz, 4H), 7.64 (d, J=8.5 Hz, 2H),8.03 (d, J=8.5 Hz, 2H); ¹⁹F NMR (CDCl₃) δ −62.65; ¹³C NMR (CDCl₃) δ15.99, 68.67, 124.13 (q, J=272.4 Hz), 125.13 (q, J=4.5 Hz), 126.89,127.28, 127.49, 128.51, 131.41 (q, J=31.8 Hz), 144.30, 144.43, 163.23.

Reference Example 14 Synthesis of(E)-N-(1-(naphthalen-1-yl)ethylidene)-1,1-diphenylmethanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (25 mL), 1-acetonaphthone (5.00 mL),benzhydrylamine (5.95 mL) and acetic acid (0.38 mL) were added thereto,and the mixture was stirred at the internal temperature of 100° C. for28 hr. The reaction mixture was cooled to 90° C., and filtered usingHirsch funnel, and the filtrate was concentrated under reduced pressureto give a brown solid. To the solid was added normal hexane (60 mL), andthe mixture was heated under reflux for 10 min, cooled to −20° C., andstirred at the same temperature for 1 hr. The resulting solid wascollected by filtration, washed with normal hexane (40 mL) cooled to−20° C., and dried under reduced pressure at 40° C. to give the titlecompound (7.82 g, yield 71%) as a white solid.

¹H NMR (CDCl₃) δ 2.50 (s, 3H), 5.22 (s, 1H), 7.02-7.05 (m, 1H),7.06-7.11 (m, 2H), 7.13-7.21 (m, 6H), 7.22-7.27 (m, 2H), 7.30-7.36 (m,1H), 7.40-7.44 (m, 1H), 7.46-7.51 (m, 2H), 7.82-7.86 (m, 1H), 7.87-7.90(m, 1H); ¹³C NMR (CDCl₃) δ 29.61, 70.19, 123.13, 125.12, 125.20, 126.31,126.47, 126.56, 126.59, 127.52, 127.74, 128.00, 128.09, 128.22, 128.45,129.09, 133.43, 137.91, 144.04, 144.48, 168.46.

Reference Example 15 Synthesis of(E)-N-(1-(furan-2-yl)ethylidene)-1,1-diphenylmethanamine

Molecular sieve 4A (4.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (20 mL), 2-acetylfuran (3.44 mL),benzhydrylamine (6.20 mL) and acetic acid (0.39 mL) were added thereto,and the mixture was stirred at the internal temperature of 90° C. for 4hr. The reaction mixture was cooled to 60° C., and filtered using Hirschfunnel, and the filtrate was concentrated under reduced pressure to givea mixture of brown liquid and white solid. To the residue was addedtoluene (20 mL), and the mixture was heated to 90° C., cooled to 0° C.,and stirred at the same temperature for 1 hr. The resulting solid wascollected by filtration, and washed with toluene (20 mL) cooled to 0° C.The obtained filtrate was concentrated under reduced pressure, toluene(10 mL) was added thereto, and the mixture was heated to 90° C., cooled,and stirred at −20° C. for 1 hr. The resulting solid was collected byfiltration, washed with toluene (8 mL) cooled to −20° C., and driedunder reduced pressure at 40° C. to give the title compound (1.50 g,yield 16%) as a white solid. ¹H NMR (CDCl₃) δ 2.24 (s, 3H), 5.83 (s,1H), 6.45 (dd, J=3.5, 2.0 Hz, 1H), 6.89 (d, J=3.5 Hz, 1H), 7.20 (t,J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz, 4H), 7.41 (d, J=7.0 Hz, 4H), 7.50 (d,J=2.0 Hz, 1H); ¹³C NMR (CDCl₃) δ 15.22, 67.91, 111.13, 111.45, 126.75,127.68, 128.42, 143.90, 144.43, 156.22 (two peaks are duplicated in oneof the underlined peaks).

Reference Example 16 Synthesis of(E)-1,1-diphenyl-N-(1-(pyridin-2-yl)ethylidene)methanamine

Toluene (50 mL), 2-acetylpyridine (5.00 mL), benzhydrylamine (8.07 mL)and acetic acid (0.51 mL) were put into a four-necked eggplant flask(100 mL) which was purged with nitrogen, and the mixture was stirred atthe internal temperature of 80° C. for 4 hr. The reaction mixture wascooled to room temperature, concentrated under reduced pressure to givean oil. To the residue was added normal hexane (50 mL), and the mixturewas stirred at 85° C. for 15 min, cooled to room temperature, andstirred at the same temperature for 1.5 hr. The resulting solid wascollected by filtration, and washed with normal hexane (20 mL). Theobtained filtrate was concentrated under reduced pressure until thevolume was reduced to about 40 mL, and left standing at −5° C. for 1 hrin a freezer. The resulting solid was washed with normal hexane (40 mL)cooled to −5° C., dried under reduced pressure at 50° C. to give thetitle compound (7.22 g, yield 57%) as pale-brown crystals.

¹H NMR (CDCl₃) δ 2.46 (s, 3H), 5.93 (s, 1H), 7.21 (t, J=7.5 Hz, 2H),7.26-7.33 (m, 5H), 7.46 (d, J=7.5 Hz, 4H), 7.73 (td, J=8.0, 2.0 Hz, 1H),8.37 (d, J=7.5 Hz, 1H), 8.56-8.60 (m, 1H); ¹³C NMR (CDCl₃) δ 14.38,68.72, 121.39, 124.19, 126.80, 127.57, 128.43, 136.17, 144.46, 148.14,157.83, 166.06.

Reference Example 17 Synthesis of(E)-1,1-diphenyl-N-(1-(pyridin-3-yl)ethylidene)methanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (25 mL), 3-acetylpyridine (5.00 mL),benzhydrylamine (8.72 mL) and acetic acid (0.52 mL) were added thereto,and the mixture was stirred at the internal temperature of 100° C. for 2hr. The reaction mixture was cooled to 80° C., and filtered using Hirschfunnel, and the filtrate was concentrated under reduced pressure to givean oil. To the residue was added toluene (20 mL), and the mixture wasstirred at 100° C. for 10 min, cooled to −20° C., and stirred at thesame temperature for 1 hr. The resulting solid was collected byfiltration, and washed with toluene (20 mL) cooled to −20° C. Theobtained filtrate was concentrated under reduced pressure, and solventsubstitution was performed with by normal hexane. The residue wasdissolved in a mixed solvent (15 mL) of normal hexane:toluene=1:2, andthe solution was cooled to −78° C., and stirred for 5 hr. The resultingsolid was collected by filtration, washed with a mixed solvent (15 mL)of normal hexane:toluene=10:1, which was cooled to −78° C., and driedunder reduced pressure at 40° C. to give the title compound (4.85 g,yield 37%) as a white solid.

¹H NMR (CDCl₃) δ 2.33 (s, 3H), 5.88 (s, 1H), 7.21 (tt, J=7.5, 1.5 Hz,2H), 7.28-7.33 (m, 5H), 7.46 (dd, J=8.0, 1.5 Hz, 4H), 8.26 (dt, J=8.0,2.0 Hz, 1H), 8.62 (dd, J=4.5, 2.0 Hz, 1H), 9.11 (d, J=2.0 Hz, 1H); ¹³CNMR (CDCl₃) δ 5.72, 68.49, 123.07, 126.87, 127.46, 128.49, 134.27,136.26, 144.39, 148.56, 150.58, 162.23.

Reference Example 18 Synthesis of(E)-1,1-diphenyl-N-(1-(thiazol-2-yl)ethylidene)methanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (25 mL), 2-acetylthiazole (5.00 mL),benzhydrylamine (8.72 mL) and acetic acid (0.55 mL) were added thereto,and the mixture was stirred at the internal temperature of 100° C. for 4hr. The reaction mixture was cooled to 70° C., and filtered using Hirschfunnel, and the filtrate was concentrated under reduced pressure to givean oil. To the residue was added normal hexane (50 mL), and the mixturewas stirred at 50° C. for 10 min, cooled to −11° C., and stirred at thesame temperature for 30 min. The resulting solid was collected byfiltration, washed with normal hexane (40 mL) cooled to −11° C., anddried under reduced pressure at 40° C. to give the title compound (10.64g, yield 75%) as a white solid.

¹H NMR (CDCl₃) δ 2.46 (s, 3H), 5.89 (s, 1H), 7.22 (t, J=7.0 Hz, 2H),7.31 (t, J=7.0 Hz, 4H), 7.38 (d, J=3.0 Hz, 1H), 7.45 (d, J=7.0 Hz, 4H),7.84 (d, J=3.0 Hz, 1H); ¹³C NMR (CDCl₃) δ 15.08, 68.29, 122.39, 126.97,127.43, 128.52, 143.29, 143.95, 160.62, 172.10.

Reference Example 19 Synthesis of (E)-methyl2-((1-benzhydrylimino)ethyl)-1,3-thiazole-5-carboxylate

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (30 mL), methyl 2-acetyl-5-thiazolecarboxylate(5.00 g), benzhydrylamine (4.90 mL) and acetic acid (0.31 mL) were addedthereto, and the mixture was stirred at the internal temperature of 100°C. for 22 hr. 4 hr after the beginning of the stirring, additionalbenzhydrylamine (0.70 mL) was added thereto. The reaction mixture wascooled to 70° C., and filtered using Hirsch funnel, and the filtrate wasconcentrated under reduced pressure to give an oil. To the residue wasadded a mixed solvent (30 mL) of normal hexane:toluene=2:1, cooled to−78° C., warmed to −20° C., and stirred for 1 hr. The resulting solidwas collected by filtration, washed with a mixed solvent (20 mL) ofnormal hexane:toluene=2:1, which was cooled to −20° C., and dried underreduced pressure at 40° C. to give the title compound (4.78 g, yield51%) as a pale-brown solid. The residual filtrate was concentrated underreduced pressure, and the residue was recrystallizd from a mixed solventof normal hexane:toluene=6:1 (14 mL) at 0° C. The resulting solid wascollected by filtration, washed with a mixed solvent of normalhexane:toluene=10:1, which was cooled to 0° C., and dried under reducedpressure at 40° C. to give the title compound (2.51 g, yield 26%) as apale-brown solid.

¹H NMR (CDCl₃) δ 2.44 (s, 3H), 3.92 (s, 3H), 5.88 (s, 1H), 7.23 (t,J=7.5 Hz, 2H), 7.32 (t, J=7.5 Hz, 4H), 7.44 (d, J=7.5 Hz, 4H), 8.39 (s,1H); ¹³C NMR (CDCl₃) δ 14.73, 52.49, 68.59, 127.14, 127.35, 128.60,131.41, 143.55, 148.62, 160.55, 161.94, 176.52.

Reference Example 20 Synthesis of(E)-N-(3,4-dihydronaphthalen-1(2H)-ylidene)-1,1-diphenylmethanamine

Molecular sieve 4A (5.00 g) was put into a four-necked eggplant flask(100 mL), and dried under reduced pressure at 100° C. for 30 min, andthe reaction system was purged with nitrogen. The flask was cooled toroom temperature, toluene (30 mL), α-tetralone (5.00 mL),benzhydrylamine (8.10 mL) and acetic acid (0.43 mL) were added thereto,and the mixture was stirred at the internal temperature of 100° C. for18 hr. The reaction mixture was cooled to 70° C., and filtered usingHirsch funnel, and the filtrate was concentrated under reduced pressureto give a brown oil. To the residue was added normal hexane (30 mL), andthe mixture was heated under reflux, cooled to 0° C., and stirred for2.5 hr. The resulting solid was collected by filtration, washed withnormal hexane (35 mL) cooled to 0° C., and dried under reduced pressureat 40° C. to give the title compound (5.90 g, yield 50%) as a whitesolid.

¹H NMR (CDCl₃) δ 1.90 (quint, J=6.5 Hz, 2H), 2.64 (t, J=6.5 Hz, 2H),2.78 (t, J=6.5 Hz, 2H), 5.88 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.18 (t,J=7.5 Hz, 2H), 7.25-7.32 (m, 6H), 7.47 (d, J=7.5 Hz, 4H), 8.50 (d, J=8.0Hz, 1H); 13C NMR (CDCl₃) δ 22.65, 28.28, 29.77, 67.05, 126.27, 126.34,126.61, 127.56, 128.27, 128.35, 129.72, 135.10, 140.59, 145.11, 163.73.

Reference Example 21 Synthesis of(E)-N-(chroman-4-ylidene)-1,1-diphenylmethanamine

Four-necked eggplant flask (100 mL) equipped with Dean-Stark trap waspurged with nitrogen, toluene (30 mL), 4-chromanone (5.00 g),benzhydrylamine (7.27 mL) and acetic acid (0.39 mL) were added thereto,and the mixture was heated under reflux at the external temperature 140°C. for 16 hr. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure, and solvent substitution wasperformed with ethanol to give an oil. To the residue was added ethanol(30 mL), and the mixture was stirred at 50° C., cooled to roomtemperature, and stirred at the same temperature for 1 hr. The resultingsolid was collected by filtration, washed with ethanol (50 mL), anddried under reduced pressure at 50° C. to give the title compound (3.71g, yield 35%) as a white solid.

¹H NMR (CDCl₃) δ 2.79 (t, J=6.0 Hz, 2H), 4.26 (t, J=6.0 Hz, 2H), 5.81(s, 1H), 6.85-6.90 (m, 1H), 6.97-7.03 (m, 1H), 7.17-7.22 (m, 2H),7.26-7.32 (m, 5H), 7.42-7.48 (m, 4H), 8.34-8.79 (m, 1H); ¹³C NMR (CDCl₃)δ 27.75, 65.68, 67.09, 117.27, 121.22, 122.92, 126.36, 126.78, 127.47,128.44, 131.85, 144.66, 158.09, 158.13.

Reference Example 22 Synthesis of N-benzhydryl-(1R)-1-phenylethanamine

(E)-1,1-Diphenyl-N-(1-phenylethylidene)methanamine (0.075 g),[Ir(cod)₂]BARF (0.0033 g) and (S)-MONOPHOS (0.0020 g) were charde in asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for 20 hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 79.4% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 5.1 min (enantiomer-A), 5.9 min (enantiomer-B)

¹H NMR (CDCl₃) δ 1.36 (d, J=7.0 Hz, 3H), 3.67 (q, J=7.0 Hz, 1H), 4.63(s, 1H), 7.15-7.19 (m, 1H), 7.22-7.29 (m, 8H), 7.31-7.36 (m, 6H) (theprotons derived from NH were not detected).

Reference Example 23 Synthesis ofN-benzhydryl-(1R)-1-(4-methoxyphenyl)ethanamine

(E)-N-(1-(4-Methoxyphenyl)ethylidene)-1,1-diphenylmethanamine (0.075 g),[Ir(cod)₂]BARF (0.0030 g) and (S)-MONOPHOS (0.0018 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 87.9% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 4.7 min (enantiomer-A), 5.5 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.34 (d, J=6.5 Hz, 3H), 3.63 (q, J=6.5 Hz, 1H), 3.82 (s,3H), 4.62 (s, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.14-7.19 (m, 3H), 7.21-7.29(m, 5H), 7.30-7.34 (m, 4H) (the protons derived from NH were notdetected).

Reference Example 24 Synthesis ofN-benzhydryl-(1R)-1-(4-chlorophenyl)ethanamine

(E)-N-(1-(4-Chlorophenyl)ethylidene)-1,1-diphenylmethanamine (0.075 g),[Ir(cod)₂]BARF (0.0030 g) and (S)-MONOPHOS (0.0018 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 96.0% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 7.6 min. (enantiomer-A), 8.8 min. (enantiomer-B)

¹H NMR (CDCl₃) δ1.34 (d, J=7.0 Hz, 3H), 3.66 (q, J=7.0 Hz, 1H), 4.58 (s,1H), 7.16-7.21 (m, 3H), 7.22-7.35 (m, 11H) (the protons derived from NHwere not detected).

Reference Example 25 Synthesis ofN-benzhydryl-(1R)-1-(4-trifluoromethylphenyl)ethanamine

(E)-1,1-Diphenyl-N-(1-(4-trifluoromethylphenyl)ethylidene)methanamine(0.075 g), [Ir(cod)₂]BARF (0.0027 g) and (S)-MONOPHOS (0.0016 g) wereput into a sample tube for an 24-hole autoclave, and the tube was set inan autoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for 20 hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 95.5% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 4.0 min (enantiomer-A), 5.4 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.36 (d, J=7.0 Hz, 3H), 3.75 (q, J=7.0 Hz, 1H), 4.58 (s,1H), 7.18 (tt, J=7.0, 1.5 Hz, 1H), 7.22-7.35 (m, 9H), 7.38 (d, J=8.5 Hz,2H), 7.58 (d, J=8.5 Hz, 2H) (the protons derived from NH were notdetected).

Reference Example 26 Synthesis ofN-benzhydryl-(1R)-1-(naphthalen-1-yl)ethanamine

(E)-N-(1-(Naphthalen-1-yl)ethylidene)-1,1-diphenylmethanamine (0.075 g),[Ir(cod)₂]BARF (0.0028 g) and (S)-MONOPHOS (0.0017 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 70.1% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 7.4 min (enantiomer-A), 9.0 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.49 (d, J=7.0 Hz, 3H), 4.56 (q, J=7.0 Hz, 1H), 4.74 (s,1H), 7.16-7.35 (m, 10H), 7.36-7.41 (m, 1H), 7.42-7.47 (m, 1H), 7.47-7.52(m, 1H), 7.66-7.70 (m, 1H), 7.74-7.78 (m, 1H), 7.84-7.91 (m, 2H) (theprotons derived from NH were not detected).

Reference Example 27 Synthesis ofN-benzhydryl-(1R)-1-(furan-2-yl)ethanamine

(E)-N-(1-(Furan-2-yl)ethylidene)-1,1-diphenylmethanamine (0.075 g),[Ir(cod)₂]BARF (0.0035 g) and (S)-MONOPHOS (0.0021 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for 20 hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 70.0% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=7/3flow rate: 1.0 mL/minretention time: 5.6 min (enantiomer-A), 6.5 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.42 (d, J=7.0 Hz, 3H), 3.73 (q, J=7.0 Hz, 1H), 4.75 (s,1H), 6.06 (d, J=3.5 Hz, 1H), 6.31 (dd, J=3.5, 1.5 Hz, 1H), 7.15-7.19 (m,1H), 7.20-7.27 (m, 3H), 7.29-7.33 (m, 4H), 7.36 (d, J=1.5 Hz, 1H),7.40-7.44 (m, 2H) (the protons derived from NH were not detected).

Reference Example 28 Synthesis ofN-benzhydryl-(1R)-1-(pyridin-2-yl)ethanamine

(E)-1,1-Diphenyl-N-(1-(pyridin-2-yl)ethylidene)methanamine (0.075 g),[Ir(cod)₂]BARF (0.0033 g) and (S)-MONOPHOS (0.0020 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 55%, 76.7% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=1/1flow rate: 1.0 mL/minretention time: 6.5 min (enantiomer-A), 8.0 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.39 (d, J=6.5 Hz, 3H), 3.78 (q, J=6.5 Hz, 1H), 4.60 (s,1H), 7.13-7.18 (m, 3H), 7.20-7.33 (m, 7H), 7.38 (d, J=7.5 Hz, 2H), 7.61(td, J=7.5, 2.0 Hz, 1H), 8.57-8.60 (m, 1H) (the protons derived from NHwere not detected).

Reference Example 29 Synthesis ofN-benzhydryl-(1R)-1-(pyridin-3-yl)ethanamine

(E)-1,1-Diphenyl-N-(1-(pyridin-3-yl)ethylidene)methanamine (0.075 g),[Ir(cod)₂]BARF (0.0033 g) and (S)-MONOPHOS (0.0020 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. By analyzing the reaction solution using high-performanceliquid chromatography and ¹H NMR, it was confirmed that the conversionwas 0%.

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OD-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=3/7, 35 min→acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2, 10 minflow rate: 1.2 mL/minretention time: 25.1 min (enantiomer-A), 27.6 min (enantiomer-B)

Reference Example 30 Synthesis ofN-benzhydryl-(1R)-1-(thiazol-2-yl)ethanamine

(E)-1,1-Diphenyl-N-(1-(thiazol-2-yl)ethylidene)methanamine (0.075 g),[Ir(cod)₂]BARF (0.0033 g) and (S)-MONOPHOS (0.0019 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 82.8% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OD-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=4/6, 35 min→acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2, 10 minflow rate: 1.2 mL/minretention time: 31.3 min (enantiomer-A), 33.2 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.53 (d, J=6.5 Hz, 3H), 4.07 (q, J=6.5 Hz, 1H), 4.92 (s,1H), 7.17-7.21 (m, 1H), 7.23-7.29 (m, 4H), 7.33 (t, J=7.5 Hz, 2H),7.36-7.40 (m, 4H), 7.73 (d, J=2.5 Hz, 1H) (the protons derived from NHwere not detected).

Reference Example 31 Synthesis of methyl2-((1R)-1-(benzhydrylamino)ethyl)-1,3-thiazole-5-carboxylate

(E)-Methyl 2-((1-Benzhydrylimino)ethyl)-1,3-thiazole-5-carboxylate(0.075 g), [Ir(cod)₂]BARF (0.0027 g) and (S)-MONOPHOS (0.0016 g) wereput into a sample tube for an 24-hole autoclave, and the tube was set inan autoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 79.7% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2 flow rate: 1.0 mL/minretention time: 4.4 min (enantiomer-A), 5.1 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.53 (d, J=6.5 Hz, 3H), 3.91 (s, 3H), 4.01 (q, J=6.5 Hz,1H), 4.95 (s, 1H), 7.18-7.23 (m, 1H), 7.23-7.30 (m, 3H), 7.32-7.36 (m,2H), 7.36-7.42 (m, 4H), 8.31 (s, 1H) (the protons derived from NH werenot detected).

Reference Example 32 Synthesis ofN-benzhydryl-1,2,3,4-tetrahydronaphthalene-(1R)-1-amine

(E)-N-(3,4-Dihydronaphthalen-1(2H)-ylidene)-1,1-diphenylmethanamine(0.075 g), [Ir(cod)₂]BARF (0.0031 g) and (S)-MONOPHOS (0.0018 g) wereput into a sample tube for an 24-hole autoclave, and the tube was set inan autoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 23.0% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 5.5 min (enantiomer-A), 8.1 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.66-1.75 (m, 1H), 1.81-2.01 (m, 3H), 2.66-2.74 (m, 1H),2.77-2.84 (m, 1H), 3.67-3.72 (m, 1H), 5.11 (s, 1H), 7.03-7.08 (m, 1H),7.11-7.24 (m, 4H), 7.25-7.30 (m, 2H), 7.30-7.36 (m, 2H), 7.43-7.49 (m,3H), 7.49-7.53 (m, 2H) (the protons derived from NH were not detected).

Reference Example 33 Synthesis of N-benzhydrylchroman-(4R)-4-amine

(E)-N-(Chroman-4-ylidene)-1,1-diphenylmethanamine (0.075 g),[Ir(cod)₂]BARF (0.0031 g) and (S)-MONOPHOS (0.0018 g) were put into asample tube for an 24-hole autoclave, and the tube was set in anautoclave. The autoclave was put in a glove box, and dichloromethane(1.5 mL) was added thereto under nitrogen atmosphere. The autoclave wassealed, and taken out of the glove box, and the reaction system waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred at 50° C. for 20 hr. Thereaction solution was cooled to room temperature, and the hydrogen wasreleased. The production of the title compound was confirmed byanalyzing the reaction solution using high-performance liquidchromatography and ¹H NMR (conversion 100%, 16.1% ee).

Conditions for High-Performance Liquid Chromatography Analysis

column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries),4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.2 mL/minretention time: 4.0 min (enantiomer-A), 4.8 min (enantiomer-B)

¹H NMR (CDCl₃) δ1.90-1.98 (m, 1H), 2.00-2.09 (m, 1H), 3.76 (t, J=5.0 Hz,1H), 4.15-4.21 (m, 1H), 4.36 (td, J=10.5, 3.0 Hz, 1H), 5.09 (s, 1H),6.79 (d, J=8.0 Hz, 1H), 6.87 (td, J=7.5, 1.5 Hz, 1H), 7.13 (td, J=7.5,1.0 Hz, 1H), 7.18-7.32 (m, 5H), 7.35 (t, J=7.5 Hz, 2H), 7.42-7.50 (m,4H) (the protons derived from NH were not detected).

Reference Example 34 Synthesis of (1R)-1-(thiazol-2-yl)ethanamine

(E)-1,1-Diphenyl-N-(1-(thiazol-2-yl)ethyl idene)methanamine (2.00 g),[Ir(cod)₂]BARF (0.0870 g) and (S)-MONOPHOS (0.0540 g) were put into anautoclave (120 mL). The atmosphere in the autoclave was decompressed,and the pressure was recovered with argon. The procedures were performedseven times in total. The pressure of the autoclave was recovered tonormal pressure, and dehydrated dichloromethane (20 mL) for organicsynthesis was fed thereto by argon pressure. Hydrogen was fed into theautoclave until the pressure was increased by 0.1 MPa, and the pressurewas recovered to normal pressure. The procedures were performed tentimes in total. Hydrogen was fed into the autoclave until 1.10 MPa, andthe mixture was stirred at the internal temperature of 50° C. for 19 hr.The mixture was cooled to the internal temperature of about 20° C., thehydrogen was released, and the atmosphere was replaced with argon(conversion 100%, optical purity 82.7% ee). The reaction solution wasconcentrated under reduced pressure, and acetonitrile (18 mL) and water(2 mL) were added thereto. N-Bromosuccinimide (1.83 g) was added theretoat near room temperature, and the mixture was stirred for 7 hr. Themixture was concentrated under reduced pressure, and the residue waspartitioned with 1 mol/L hydrochloric acid (10 mL) and ethyl acetate (20mL) (organic layer (1) and aqueous layer (1)). The aqueous layer (1) wasadjusted to pH 5 with 5 mol/L aqueous sodium hydroxide solution (about 3mL), and extracted with ethyl acetate (20 mL) (organic layer (2) andaqueous layer (2)). The aqueous layer (2) was partitioned with κ mol/Laqueous sodium hydroxide solution (1 mL) and ethyl acetate (20 mL)(organic layer (3) and aqueous layer (3)). The organic layer (3) waswashed with saturated brine (10 mL) (organic layer (4) and aqueous layer(4)). The organic layer (1) was washed with saturated brine (10 mL)(organic layer (5) and aqueous layer (5)). The aqueous layer (4) andaqueous layer (5) were combined, and extracted with ethyl acetate (30mL) (organic layer (6) and aqueous layer (6)). The organic layer (4),organic layer (5) and organic layer (6) were combined, and dried overmagnesium sulfate. The magnesium sulfate was removed by filtration, andthe filtrate was concentrated under reduced pressure to give the titlecompound. brown oil, 0.61 g, yield 70.1%, HPLC area normalization 89.7%.

Conditions for High-Performance Liquid Chromatography Analysis (areanormalization)column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.4 min (the title compound)

¹H NMR (CDCl₃) δ 1.54 (d, J=6.6 Hz, 3H), 4.42 (q, J=6.6 Hz, 1H), 7.23(d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H). ¹³C NMR (CDCl₃) δ 24.66,49.65, 118.36, 142.38, 178.38.

Reference Example 35 Synthesis of(R)-methyl-2-(1-aminoethyl)-1,3-thiazole-5-carboxylatep-toluenesulfonate

(E)-Methyl 2-((1-benzhydrylimino)ethyl)-1,3-thiazole-5-carboxylate (1.00g), [Ir(cod)₂]BARF (0.0363 g) and (S)-MONOPHOS (0.0226 g) were put intoan autoclave (120 mL). The atmosphere in the autoclave was decompressed,and the pressure was recovered with argon. The procedures were performedseven times in total. The pressure of the autoclave was recovered tonormal pressure, and dehydrated dichloromethane (20 mL) for organicsynthesis was fed thereto by argon pressure. Hydrogen was fed into theautoclave until the pressure was increased by 0.1 MPa, and the pressurewas recovered to normal pressure. The procedures were performed tentimes in total. Hydrogen was fed into the autoclave until 1.0 MPa, andthe mixture was stirred at the internal temperature of 50° C. for 18 hr.The mixture was cooled to the internal temperature of about 20° C., thehydrogen was released, and the atmosphere was replaced with argon(conversion 100%, optical purity 80.1% ee). The reaction solution wasconcentrated under reduced pressure, and acetonitrile (9 mL), water (1mL) and N-bromosuccinimide (0.61 g) were thereto at near roomtemperature, and the mixture was stirred for 23 hr. The mixture wasconcentrated under reduced pressure, and the residue was partitionedwith water (3 mL) and ethyl acetate (10 mL) (organic layer (1) andaqueous layer (1)). The aqueous layer (1) was partitioned with 1 mol/Laqueous sodium hydroxide solution (3 mL) and ethyl acetate (15 mL)(organic layer (2) and aqueous layer (2)). The aqueous layer (2) waspartitioned with 1 mol/L aqueous sodium hydroxide solution (1 mL) andethyl acetate (10 mL) (organic layer (3) and aqueous layer (3)). Theorganic layer (2) and organic layer (3) were combined, andp-toluenesulfonic acid monohydrate (0.56 g) was added thereto. Themixture was concentrated under reduced pressure, acetonitrile (10 mL)was added thereto, and the mixture was stirred at the temperature ofnear room temperature for 1 hr. The crystallized substance was collectedby filtration, and washed with acetonitrile, and dried under reducedpressure at 50° C. to give the title compound. pale yellow powder,0.6412 g, yield 62.7%, HPLC area normalization 100%, optical purity80.3% ee.

Conditions for High-Performance Liquid Chromatography Analysis (HPLCarea normalization)column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.2 min (the title compound)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: CHIRALPAK IA (manufactured by Daicel Chemical Industries),4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol for high-performance liquidchromatography/distilled water for high-performance liquidchromatography-80/15/5flow rate: 1.0 mL/minretention time: 4.5 min (enantiomer-A), 5.7 min (enantiomer-B)

¹H NMR (DMSO-d₆) δ 1.61 (d, J=6.9 Hz, 3H), 2.29 (s, 3H), 3.87 (s, 3H),4.95 (q, J=6.8 Hz, 1H), 7.12 (d, J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H),8.51 (s, 1H), 8.64 (brs, 3H). ¹³C NMR (DMSO-d₆) δ 19.76, 20.74, 47.62,52.79, 125.45, 128.04, 130.01, 137.73, 145.44, 147.56, 160.80, 172.89.

Examples 163-368 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(substrate, 0.0350 g), an ammonium salt (amine source, 10 equivalentrelative to the substrate), a metal source (0.05 equivalent relative tothe substrate) and a ligand (1.1 equivalent realtive to the metalsource) were each weighed, and they were put into a test tube for a24-hole autoclave. A solvent (1.5 mL) was added thereto under nitrogenatmosphere, and the atmosphere in the autoclave was purged withhydrogen. Hydrogen was fed into the autoclave until 3.0 MPa, and themixture was stirred at 50° C. for 22 hr. After the completion of thereaction, the autoclave was cooled, and the hydrogen gas was released.The selectivity of the title compound (containing R-form and S-form) andthe enantiomeric excess (ee) of the title compound (R-form) werecalculated from HPLC. The results are shown in Table 16-Table 20. Thestructure of the ligand used above is shown above. In Examples 348-355and 359-361, (−)-CSA is used in an amount of 0.1 equivalent relative tothe substrate, as an additive.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.3 min. (the title compound (containing R-form andS-form)), 2.9 min. (alcohol form), 4.8 min. (substrate) conditions forhigh-performance liquid chromatography analysis (optical purity)column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 1.0 mL/mincolumn temperature: 40° C.retention time: 4.6 min. (substrate), 5.8 min. (alcohol form), 11.6 min.(alcohol form), 16.2 min. (the title compound (R-form)), 24.2 min.(enantiomer (S-form) of the title compound).

TABLE 16 amine title com- alcohol % selectivity Ex. metal source ligandsource solvent pound (%)* form (%) ee Stereo (%)** 163 [Rh(cod)₂]OTf(R)-BINAP Ammonium MeOH 42.1 26.1 5.4 S 92.1 acetate 164 [Rh(cod)₂]OTf(R)-Xylyl-BINAP Ammonium MeOH 49.7 20.5 4.2 S 94.5 acetate 165[Rh(cod)₂]OTf (R,R)-DIPAMP Ammonium MeOH 16.3 31.5 3.3 S 49.8 acetate166 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium MeOH 63.7 25.1 1.0 S 76.1acetate 167 [Rh(cod)₂]OTf (S,S)-PTBP- Ammonium MeOH 56.4 33.4 1.0 S 64.5SKEWPHOS acetate 168 [Rh(cod)₂]OTf (R)(S)-JOSIPHOS Ammonium MeOH 70.017.5 1.4 S 90.8 acetate 169 [Rh(cod)₂]OTf (R,R)-iPr-DUPHOS Ammonium MeOH21.8 32.8 0.6 S 55.2 acetate 170 [Rh(cod)₂]OTf (R)-PHANEPHOS AmmoniumMeOH 73.7 17.7 1.2 R 86.5 acetate 171 [Rh(cod)₂]OTf (R,R)-Me- AmmoniumMeOH 45.4 48.0 10.4 S 49.4 Ferrocelane acetate 172 [RhCl(cod)]₂(R)-BINAP Ammonium MeOH 41.7 19.7 4.2 S 94.2 acetate 173 [RhCl(cod)]₂(R)-Xylyl-BINAP Ammonium MeOH 52.6 20.1 3.8 S 95.1 acetate 174[RhCl(cod)]₂ (R,R)-DIPAMP Ammonium MeOH 23.4 30.8 4.1 S 62.6 acetate 175[RhCl(cod)]₂ (R,R)-Skewphos Ammonium MeOH 62.3 26.5 0.6 S 74.3 acetate176 [RhCl(cod)]₂ (S,S)-PTBP- Ammonium MeOH 54.6 34.2 4.6 S 63.6 SKEWPHOSacetate 177 [RhCl(cod)]₂ (R)(S)-JOSIPHOS Ammonium MeOH 53.7 21.7 6.2 S87.2 acetate 178 [RhCl(cod)]₂ (R,R)-iPr-DUPHOS Ammonium MeOH 14.5 29.93.0 R 43.3 acetate 179 [RhCl(cod)]₂ (R)-PHANEPHOS Ammonium MeOH 72.018.7 0.8 R 85.4 acetate 180 [RhCl(cod)]₂ (R,R)-Me- Ammonium MeOH 59.731.4 9.5 S 69.1 Ferrocelane acetate 181 [RH(cod)₂]OTf (R)-Xylyl-BINAPAmmonium MeOH 9.4 6.6 11.1 S nd salicylate 182 [Rh(cod)₂]OTf(R,R)-CHIRAPHOS Ammonium MeOH 35.4 21.4 1.5 S 58.0 salicylate 183[Rh(cod)₂]OTf (R,R)-DIPAMP Ammonium MeOH 24.1 26.5 8.2 S 39.3 salicylate184 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium MeOH 54.4 15.1 6.3 R 76.6salicylate 185 [Rh(cod)₂]OTf (S,S)-PTBP- Ammonium MeOH 55.0 17.5 10.7 S74.4 SKEWPHOS salicylate 186 [Rh(cod)₂]OTf (R)(S)-JOSIPHOS Ammonium MeOH41.3 8.7 9.2 S 86.4 salicylate 187 [Rh(cod)₂]OTf (R,R)-iPr-DUPHOSAmmonium MeOH 14.9 24.4 10.3 S 28.6 salicylate 188 [Rh(cod)₂]OTf(R)-PHANEPHOS Ammonium MeOH 65.4 4.5 3.2 R 96.0 salicylate 189[Rh(cod)₂]OTf (R,R)-Me- Ammonium MeOH 32.8 34.8 11.5 S 41.0 Ferrocelanesalicylate 190 [RhCl(cod)]₂ (R)-Xylyl-BINAP Ammonium MeOH 11.6 6.5 25.7S nd salicylate 191 [RhCl(cod)]₂ (R,R)-CHIRAPHOS Ammonium MeOH 27.3 28.79.3 S 40.1 salicylate 192 [RhCl(cod)]₂ (R,R)-DIPAMP Ammonium MeOH 26.024.9 8.4 S 43.0 salicylate 193 [RhCl(cod)]₂ (R,R)-Skewphos Ammonium MeOH55.5 16.1 8.3 R 74.7 salicylate 194 [RhCl(cod)]₂ (S,S)-PTBP- AmmoniumMeOH 54.1 18.7 21.6 S 71.3 SKEWPHOS salicylate 195 [RhCl(cod)]₂(R)(S)-JOSIPHOS Ammonium MeOH 42.3 11.8 4.3 S 77.6 salicylate 196[RhCl(cod)]₂ (R,R)-Ph-BPE Ammonium MeOH 20.9 4.0 10.7 S nd salicylate197 [RhCl(cod)]₂ (R,R)-iPr-DUPHOS Ammonium MeOH 16.9 25.5 9.7 S 30.4salicylate 198 [RhCl(cod)]₂ (R)-PHANEPHOS Ammonium MeOH 67.0 4.6 7.5 R95.9 salicylate 199 [RhCl(cod)]₂ (R,R)-Me- Ammonium MeOH 37.6 15.5 9.2 S69.4 Ferrocelane salicylate 200 [Rh(cod)₂]OTf (R,R)-Skewphos AmmoniumIPA 57.2 9.6 23.7 R 85.6 salicylate 201 [Rh(cod)₂]OTf (R)(S)-JOSIPHOSAmmonium IPA 45.2 4.2 8.2 S 93.9 salicylate 202 [Rh(cod)₂]OTf(R)-PHANEPHOS Ammonium IPA 59.3 6.0 3.1 R 90.2 salicylate 203[Rh(cod)₂]OTf (R,R)-Me- Ammonium IPA 21.1 9.9 10.6 S 63.5 Ferrocelanesalicylate 204 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium TFE 7.0 3.5 6.9 R78.7 salicylate 205 [Rh(cod)₂]OTf (R)(S)-JOSIPHOS Ammonium TFE 6.4 20.74.4 S 19.1 salicylate 206 [Rh(cod)₂]OTf (R)-PHANEPHOS Ammonium TFE 5.22.8 0.4 R 60.2 salicylate 207 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium THF72.8 2.2 8.0 S 97.4 salicylate 208 [Rh(cod)₂]OTf (R)(S)-JOSIPHOSAmmonium THF 64.1 2.3 19.0 S 98.6 salicylate 209 [Rh(cod)₂]OTf(R)-PHANEPHOS Ammonium THF 75.4 1.2 13.9 S 100.0 salicylate 210[Rh(cod)₂]OTf (R,R)-Me- Ammonium THF 72.3 4.1 22.6 S 97.0 Ferrocelanesalicylate 211 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium EtOAc 52.0 9.7 5.2S 82.7 salicylate 212 [Rh(cod)₂]OTf (R)(S)-JOSIPHOS Ammonium EtOAc 37.89.9 23.6 S 76.6 salicylate 213 [Rh(cod)₂]OTf (R)-PHANEPHOS AmmoniumEtOAc 58.2 4.8 11.8 S 91.8 salicylate 214 [Rh(cod)₂]OTf (R,R)-Me-Ammonium EtOAc 34.4 31.5 18.6 S 45.4 Ferrocelane salicylate 215[Rh(cod)₂]OTf (R)-PHANEPHOS Ammonium DCM 11.7 12.4 9.7 S 37.9 salicylate216 [Rh(cod)₂]OTf (R,R)-Me- Ammonium DCM 2.6 72.3 6.8 S 2.2 Ferrocelanesalicylate 217 [Rh(cod)₂]OTf (R,R)-Skewphos Ammonium Toluene 5.0 4.217.2 R 47.9 salicylate 218 [Rh(cod)₂]OTf (R)(S)-JOSIPHOS AmmoniumToluene 4.7 19.7 38.0 S 4.3 salicylate 219 [Rh(cod)₂]OTf (R)-PHANEPHOSAmmonium Toluene 5.6 5.7 30.8 R 31.9 salicylate 220 [Rh(cod)₂]OTf(R,R)-Me- Ammonium Toluene 3.6 25.9 17.3 S 9.8 Ferrocelane salicylate221 [Rh(cod)₂]OTf (S,S)-PTBP- Ammonium IPA 50.3 9.3 8.2 S 84.5 SKEWPHOSsalicylate 222 [Rh(cod)₂]OTf (S,S)-Xylyl- Ammonium MeOH 50.2 21.5 1.1 S70.0 Skewphos salicylate 224 [Rh(cod)₂]OTf SL-J002-1 Ammonium MeOH 40.411.8 0.3 S 82.3 salicylate 225 [Rh(cod)₂]OTf SL-J004-1 Ammonium MeOH42.3 10.9 0.3 S 81.3 salicylate 226 [Rh(cod)₂]OTf SL-J005-1 AmmoniumMeOH 49.7 6.5 0.8 S 91.4 salicylate 227 [Rh(cod)₂]OTf SL-J009-1 AmmoniumMeOH 26.3 49.3 18.2 R 33.9 salicylate 228 [Rh(cod)₂]OTf SL-J212-1Ammonium MeOH 44.5 5.9 1.7 S 93.2 salicylate 229 [Rh(cod)₂]OTf SL-T001-1Ammonium MeOH 54.1 13.9 2.5 R 81.8 salicylate 230 [Rh(cod)₂]OTfSL-W001-1 Ammonium MeOH 58.7 6.6 17.0 S 97.2 salicylate 231[Rh(cod)₂]OTf SL-M001-1 Ammonium MeOH 59.3 5.5 38.3 S 91.6 salicylate232 [Rh(cod)₂]OTf SL-M002-1 Ammonium MeOH 40.7 17.3 9.8 S 71.6salicylate 233 [Rh(cod)₂]OTf (S,S)-PTBP- Ammonium THF 73.1 3.0 9.3 S95.5 SKEWPHOS salicylate 234 [Rh(cod)₂]OTf (S,S)-Xylyl- Ammonium THF57.2 16.3 16.2 S 81.7 Skewphos salicylate 236 [Rh(cod)₂]OTf SL-J002-1Ammonium THF 72.1 2.8 44.5 S 92.4 salicylate 237 [Rh(cod)₂]OTf SL-J004-1Ammonium THF 32.1 1.9 65.6 S 100.0 salicylate 238 [Rh(cod)₂]OTfSL-J005-1 Ammonium THF 57.8 1.5 4.7 S 96.9 salicylate 239 [Rh(cod)₂]OTfSL-J009-1 Ammonium THF 53.3 19.7 47.9 S 69.6 salicylate 240[Rh(cod)₂]OTf SL-J212-1 Ammonium THF 65.6 1.3 15.5 S 100.0 salicylate241 [Rh(cod)₂]OTf SL-T001-1 Ammonium THF 73.2 1.3 4.0 S 100.0 salicylate242 [Rh(cod)₂]OTf SL-W001-1 Ammonium THF 73.1 3.9 13.3 S 100.0salicylate 243 [Rh(cod)₂]OTf SL-M001-1 Ammonium THF 73.9 0.7 7.7 S 100.0salicylate 244 [Rh(cod)₂]OTf SL-M002-1 Ammonium THF 62.2 3.3 22.3 S 96.0salicylate *the title compound (containing R-form and S-form)**selectivity (%) = 100 × the title compound (R form + S-form)/(alcoholform + the title compound (R form + S-form))

TABLE 17 amine title alcohol selectivity Ex. metal source ligand sourcesolvent compound (%)* form (%) % ee Stereo (%)** 245 [Ir(cod)₂]BARF(R)-BINAP Ammonium MeOH 20.1 71.4 3.9 S 23.1 acetate 246 [Ir(cod)₂]BARF(R)-Xylyl- Ammonium MeOH 56.0 31.5 0.7 S 70.1 BINAP acetate 247[Ir(cod)₂]BARF (R,R)- Ammonium MeOH 10.8 24.9 0.4 S 47.8 CHIRAPHOSacetate 248 [Ir(cod)₂]BARF (R,R)- Ammonium MeOH 46.6 43.9 1.7 R 55.1Skewphos acetate 249 [Ir(cod)₂]BARF (S,S)-PTBP- Ammonium MeOH 57.8 35.51.0 S 68.3 SKEWPHOS acetate 250 [Ir(cod)₂]BARF (R)(S)- Ammonium MeOH44.4 45.6 0.5 R 54.1 JOSIPHOS acetate 251 [Ir(cod)₂]BARF (R,R)-iPr-Ammonium MeOH 27.0 47.1 0.7 R 43.3 DUPHOS acetate 252 [Ir(cod)₂]BARF(R)- Ammonium MeOH 5.7 59.0 14.4 S 5.0 PHANEPHOS acetate 253[Ir(cod)₂]BARF (R,R)-Me- Ammonium MeOH 36.1 51.6 2.5 R 45.6 Ferrocelaneacetate 254 [IrCl(cod)]₂ (R)-BINAP Ammonium MeOH 20.2 66.0 6.9 S 24.0acetate 255 [IrCl(cod)]₂ (R)-Xylyl- Ammonium MeOH 29.8 44.1 4.0 S 45.2BINAP acetate 256 [IrCl(cod)]₂ (R,R)- Ammonium MeOH 30.7 52.4 1.7 R 37.5CHIPAPHOS acetate 257 [IrCl(cod)]₂ (R,R)-DIPAMP Ammonium MeOH 52.0 35.11.0 R 64.0 acetate 258 [IrCl(cod)]₂ (R,R)- Ammonium MeOH 49.2 41.6 1.8 R57.4 Skewphos acetate 259 [IrCl(cod)]₂ (S,S)-PTBP- Ammonium MeOH 60.232.2 2.6 S 71.7 SKEWPHOS acetate 260 [IrCl(cod)]₂ (R)(S)- Ammonium MeOH28.8 58.6 1.3 R 34.7 JOSIPHOS acetate 261 [IrCl(cod)]₂ (R)-iPr-PHOXAmmonium MeOH 3.8 48.9 2.4 S 3.1 acetate 262 [IrCl(cod)]₂ (R,R)-iPr-Ammonium MeOH 32.8 44.5 1.4 R 51.2 DUPHOS acetate 263 [IrCl(cod)]₂ (R)-Ammonium MeOH 27.3 64.5 2.0 S 29.2 PHANEPHOS acetate 264 [IrCl(cod)]₂(R,R)-Me- Ammonium MeOH 39.1 49.3 0.2 S 46.2 Ferrocelane acetate 265[IrCl(cod)]₂ (R)-MONOPHOS Ammonium MeOH 3.5 55.5 0.9 S 2.3 acetate 266[Ir(cod)₂]BARF (R)-BINAP Ammonium MeOH 25.4 35.3 0.4 S 39.5 salicylate267 [Ir(cod)₂]BARF (R)-Xylyl- Ammonium MeOH 35.1 24.4 0.2 R 58.7 BINAPsalicylate 268 [Ir(cod)₂]BARF (R,R)- Ammonium MeOH 29.2 33.2 1.4 R 45.7CHIRAPHOS salicylate 269 [Ir(cod)₂]BARF (R,R)-DIPAMP Ammonium MeOH 38.513.1 1.1 R 75.9 salicylate 270 [Ir(cod)₂]BARF (R,R)- Ammonium MeOH 36.015.5 0.1 S 70.2 Skewphos salicylate 271 [Ir(cod)₂]BARF (S,S)-PTBP-Ammonium MeOH 36.2 16.8 0.6 S 68.0 SKEWPHOS salicylate 272[Ir(cod)₂]BARF (R)(S)- Ammonium MeOH 51.9 13.8 1.1 R 81.3 JOSIPHOSsalicylate 273 [Ir(cod)₂]BARF (R)-iPr-PHOX Ammonium MeOH 4.3 9.0 1.4 R23.9 salicylate 274 [Ir(cod)₂]BARF (R,R)-iPr- Ammonium MeOH 25.1 35.21.0 S 41.0 DUPHOS salicylate 275 [Ir(cod)₂]BARF (R)- Ammonium MeOH 14.624.0 0.8 S 36.6 PHANEPHOS salicylate 276 [Ir(cod)₂]BARF (R,R)-Me-Ammonium MeOH 38.0 19.7 0.4 S 69.2 Ferrocelane salicylate 277[Ir(cod)₂]BARF (R)-MONOPHOS Ammonium MeOH 38.0 18.1 0.5 S 68.4salicylate 278 [IrCl(cod)]₂ (R)-BINAP Ammonium MeOH 49.7 15.5 8.2 S 78.0salicylate 279 [IrCl(cod)]₂ (R)-Xylyl-BINAP Ammonium MeOH 20.4 40.7 0.9S 29.8 salicylate 280 [IrCl(cod)]₂ (R,R)- Ammonium MeOH 11.8 16.8 3.0 S41.2 CHIRAPHOS salicylate 281 [IrCl(cod)]₂ (R,R)-DIPAMP Ammonium MeOH20.0 13.4 2.4 S 60.9 salicylate 282 [IrCl(cod)]₂ (R,R)- Ammonium MeOH64.5 9.6 22.6 R 89.1 Skewphos salicylate 283 [IrCl(cod)]₂ (S,S)-PTBP-Ammonium MeOH 62.6 10.7 32.1 S 87.0 SKEWPHOS salicylate 284 [IrCl(cod)]₂(R) (S)- Ammonium MeOH 36.3 28.8 2.0 S 55.2 JOSIPHOS salicylate 285[IrCl(cod)]₂ (R)-iPr-PHOX Ammonium MeOH 36.4 10.6 4.4 S 72.1 salicylate286 [IrCl(cod)]₂ (R,R)-iPr- Ammonium MeOH 21.6 27.0 9.5 S 44.6 DUPHOSsalicylate 287 [IrCl(cod)]₂ (R)- Ammonium MeOH 18.5 11.9 8.9 S 64.3PHANEPHOS salicylate 288 [IrCl(cod)]₂ (R,R)-Me- Ammonium MeOH 39.9 12.22.3 S 82.4 Ferrocelane salicylate 289 [IrCl(cod)]₂ (R)-MONOPHOS AmmoniumMeOH 8.3 13.0 9.9 S 37.4 salicylate 290 [IrCl(cod)]₂ (R,R)- AmmoniumMeOH 51.0 14.9 0.1 R 76.6 Skewphos salicylate 291 [IrCl(cod)]₂(S,S)-PTBP- Ammonium MeOH 63.6 10.9 16.1 S 86.5 SKEWPHOS salicylate 292[IrCl(cod)]₂ (S,S)-Xylyl- Ammonium MeOH 61.4 10.7 3.1 S 86.2 Skewphossalicylate 293 [IrCl(cod)]₂ (R,R)- Ammonium IPA 66.4 5.4 74.6 R 92.6Skewphos salicylate 294 [IrCl(cod)]₂ (S,S)-PTBP- Ammonium IPA 67.9 2.887.4 S 96.3 SKEWPHOS salicylate 295 [IrCl(cod)]₂ (S,S)-Xylyl- AmmoniumIPA 64.3 3.9 27.0 S 94.7 Skewphos salicylate 296 [IrCl(cod)]₂ (R,R)-Ammonium THF 70.8 4.4 35.4 R 93.8 Skewphos salicylate 297 [IrCl(cod)]₂(S,S)-PTBP- Ammonium THF 73.6 3.6 59.9. S 96.0 SKEWPHOS salicylate 298[IrCl(cod)]₂ (S,S)-Xylyl- Ammonium THF 53.0 7.2 19.2 S 86.7 Skewphossalicylate 299 [IrCl(cod)]₂ (R,R)- Ammonium DCM/ 70.3 5.9 7.0 R 93.3Skewphos salicylate MeOH = 2/1 300 [IrCl(cod)]₂ (S,S)-PTBP- AmmoniumDCM/ 61.7 5.5 14.9 S 92.2 SKEWPHOS salicylate MeOH = 2/1 301[IrCl(cod)]₂ (S,S)-Xylyl- Ammonium DCM/ 46.1 7.8 1.0 S 84.7 Skewphossalicylate MeOH = 2/1 302 [IrCl(cod)]₂ (R,R)- Ammonium Toulene/ 33.1 3.023.9 R nd Skewphos salicylate MeOH = 2/1 303 [IrCl(cod)]₂ (S,S)-PTBP-Ammonium Toulene/ 35.0 1.8 43.5 S 96.0 SKEWPHOS salicylate MeOH = 2/1304 [IrCl(cod)]₂ (S,S)-Xylyl- Ammonium Toulene/ 31.3 4.0 6.2 S 88.2Skewphos salicylate MeOH = 2/1 305 [IrCl(cod)]₂ (R,R)- Ammonium TFE 11.026.5 6.4 S 26.6 Skewphos salicylate 306 [IrCl(cod)]₂ (S,S)-PTBP-Ammonium TFE 6.5 38.1 4.5 S 11.6 SKEWPHOS salicylate 307 [IrCl(cod)]₂(S,S)-PTBP- Ammonium IPA 70.0 2.0 75.9 S 97.8 SKEWPHOS salicylate 308[IrCl(cod)]₂ (S,S)-PMP- Ammonium IPA 63.9 1.9 71.6 S 96.8 SKEWPHOSsalicylate 309 [IrCl(cod)]₂ (R,R)-PDA- Ammonium IPA 43.8 5.2 35.0 R 89.1Skewphos salicylate 310 [IrCl(cod)]₂ (S,S)-PTBP- Ammonium IPA 68.1 1.978.3 S 98.1 SKEWPHOS salicylate 311 [IrCl(cod)]₂ (S,S)-PMP- Ammonium IPA62.1 1.8 73.0 S 96.9 SKEWPHOS salicylate 312 [IrCl(cod)]₂ (R,R)-PDA-Ammonium IPA 32.0 5.5 29.9 R 84.2 Skewphos salicylate 313 [IrCl(cod)]₂SL-J002-1 Ammonium IPA 6.6 7.7 11.6 R 39.1 salicylate 314 [IrCl(cod)]₂SL-J003-1 Ammonium IPA 6.6 7.9 2.1 R 36.5 salicylate 315 [IrCl(cod)]₂SL-J004-1 Ammonium IPA 37.5 3.9 3.7 R 90.3 salicylate 316 [IrCl(cod)]₂SL-J009-1 Ammonium IPA 9.2 11.1 0.0 R 61.3 salicylate 317 [IrCl(cod)]₂SL-J502-1 Ammonium IPA 3.6 14.0 0.0 R 8.3 salicylate 318 [IrCl(cod)]₂SL-J005-1 Ammonium IPA 52.8 3.3 39.6 R 94.7 salicylate 319 [IrCl(cod)]₂SL-J006-1 Ammonium IPA 9.7 4.9 0.6 R 60.7 salicylate 320 [IrCl(cod)]₂SL-J007-1 Ammonium IPA 26.1 5.5 0.2 R 82.2 salicylate 321 [IrCl(cod)]₂SL-J011-1 Ammonium IPA 5.5 8.2 0.3 S 31.7 salicylate 322 [IrCl(cod)]₂SL-J212-1 Ammonium IPA 4.6 9.0 2.0 S 26.4 salicylate 323 [IrCl(cod)]₂SL-J202-1 Ammonium IPA 8.7 6.1 0.8 S 69.6 salicylate 324 [IrCl(cod)]₂SL-J013-1 Ammonium IPA 7.9 7.9 1.8 S 47.0 salicylate 325 [IrCl(cod)]₂SL-J216-1 Ammonium IPA 37.4 3.9 1.4 S 90.5 salicylate 326 [IrCl(cod)]₂SL-J210-1 Ammonium IPA 2.2 7.8 3.9 S 21.7 salicylate 327 [IrCl(cod)]₂SL-J203-2 Ammonium IPA 9.0 8.1 2.2 S 37.5 salicylate 328 [IrCl(cod)]₂R-Bophoz Ammonium IPA 36.1 5.1 2.7 S 89.0 salicylate *the title compound(containing R-form and S-form) **selectivity (%) = 100 × the titlecompound (R form + S-form)/(alcohol form + the title compound (R form +S-form))

TABLE 18 title alcohol selectivity Ex. metal source ligand amine sourcesolvent compound (%)* form (%) % ee Stereo (%)** 329 [Ir(cod)₂]BARF(R,R)- Ammonium IPA 42.5 11.4 2.6 R 78.2 Skewphos salicylate 330[Ir(cod)₂]BARF (S,S)-PTBP- Ammonium IPA 0.3 55.0 4.3 S 83.2 SKEWPHOSsalicylate 331 [IrCl(cod)]₂ (R,R)- Ammonium IPA 0.3 63.8 67.8 R 94.7Skewphos salicylate 332 [IrCl(cod)]₂ (S,S)-PTBP- Ammonium IPA 0.3 70.880.1 S 97.9 SKEWPHOS salicylate 333 [RhCl(cod)]₂ (R,R)- Ammonium IPA 0.38.7 5.5 S 58.1 Skewphos salicylate 334 [RhCl(cod)]₂ (S,S)-PTBP- AmmoniumIPA 0.5 71.0 32.7 S 83.4 SKEWPHOS salicylate 335 [Rh(cod)₂]OTf (R,R)-Ammonium IPA 0.2 49.2 4.7 R 88.6 Skewphos salicylate 336 [Rh(cod)₂]OTf(S,S)-PTBP- Ammonium IPA 0.3 58.1 24.7 S 81.3 SKEWPHOS salicylate 337[Ir(cod)₂]BARF (R,R)- Ammonium THF 0.2 73.8 35.1 R 93.4 Skewphossalicylate 338 [Ir(cod)₂]BARF (S,S)-PTBP- Ammonium THF 0.2 76.8 38.9 S95.9 SKEWPHOS salicylate 339 [IrCl(cod)]₂ (R,R)- Ammonium THF 0.2 74.135.4 R 92.3 Skewphos salicylate 340 [IrCl(cod)]₂ (S,S)-PTBP- AmmoniumTHF 0.2 77.0 62.1 S 95.6 SKEWPHOS salicylate 341 [RhCl(cod)]₂ (R,R)-Ammonium THF 0.1 72.4 7.4 S 96.1 Skewphos salicylate 342 [RhCl(cod)]₂(S,S)-PTBP- Ammonium THF 0.2 77.0 22.0 S 96.8 SKEWPHOS salicylate 343[Rh(cod)₂]OTf (R,R)- Ammonium THF 0.2 75.4 1.6 S 96.7 Skewphossalicylate 343 [Rh(cod)₂]OTf (S,S)-PTBP- Ammonium THF 0.2 76.7 2.4 S96.2 SKEWPHOS salicylate *the title compound (containing R-form andS-form) **selectivity (%) = 100 × the title compound (R form +S-form)/(alcohol form + the title compound (R form + S-form))

TABLE 19 metal amine title com- alcohol selectivity Ex. source ligandsource solvent Additive pound (%)* form (%) % ee Stereo (%)** 345Pd(OAc)₂ (R)-BINAP Ammonium MeOH — 52.6 2.8 4.0 R 96.5 salicylate 346Pd(OAc)₂ (R,R)- Ammonium MeOH — 11.9 3.7 1.1 S nd Skewphos salicylate347 Pd(OAc)₂ (R)(S)- Ammonium MeOH — 28.5 2.6 1.2 S 97.1 JOSIPHOSsalicylate 348 Pd(OAc)₂ (R)-BINAP Ammonium MeOH (−)-CSA 50.3 2.2 10.8 Snd salicylate 0.1 eq. 349 Pd(OAc)₂ (R,R)- Ammonium MeOH (−)-CSA 12.9 4.325.2 S nd Skewphos salicylate 0.1 eq. 350 Pd(OAc)₂ (R)(S)- Ammonium MeOH(−)-CSA 20.7 3.7 18.4 S nd JOSIPHOS salicylate 0.1 eq. 351 Pd(OAc)₂ (R)-Ammonium MeOH (−)-CSA 8.7 3.8 10.4 R nd PHANEPHOS salicylate 0.1 eq. 352Pd(OAc)₂ (R)-BINAP Ammonium MeOH (−)-CSA 41.5 1.8 12.5 R nd salicylate1.0 eq. 353 Pd(OAc)₂ (R,R)- Ammonium MeOH (−)-CSA 40.7 2.5 9.5 R ndSkewphos salicylate 1.0 eq. 354 Pd(OAc)₂ (R)(S)- Ammonium MeOH (−)-CSA10.8 2.8 15.2 R nd JOSIPHOS salicylate 1.0 eq. 355 Pd(OAc)₂ (R)-Ammonium MeOH (−)-CSA 44.3 1.8 12.7 R nd PHANEPHOS salicylate 1.0 eq.356 Pd(OAc)₂ (R)-BINAP Ammonium THF — 16.0 0.4 7.1 S nd salicylate 357Pd(OAc)₂ (R,R)- Ammonium THF — 3.9 0.7 2.8 S nd Skewphos salicylate 358Pd(OAc)₂ (R)- Ammonium THF — 19.7 0.3 2.4 S nd PHANEPHOS salicylate 359Pd(OAc)₂ (R)-BINAP Ammonium THF (−)-CSA 27.9 0.4 22.5 S nd salicylate0.1 eq. 360 Pd(OAc)₂ (R)- Ammonium THF (−)-CSA 38.7 0.2 22.9 S ndPHANEPHOS salicylate 0.1 eq. 361 Pd(OAc)₂ (R)- Ammonium THF (−)-CSA 13.80.3 34.5 R nd PHANEPHOS salicylate 0.1 eq. *the title compound(containing R-form and S-form) **selectivity (%) = 100 × the titlecompound (R form + S-form)/(alcohol form + the title compound (R form +S-form))

TABLE 20 metal amine title com- alcohol selectivity Ex. source ligandsource solvent pound (%)* form (%) % ee Stereo (%)** 362 [IrCl(cod)]₂(R,R)-PTBP- Ammonium IPA 68.1 2.5 77.5 R 98.2 SKEWPHOS salicylate 363[IrCl(cod)]₂ (R,R)-PTBP- Ammonium IPA 40.5 45.3 32.5 R 44.7 SKEWPHOScarbonate 364 [IrCl(cod)]₂ (R,R)-PTBP- Ammonium IPA 27.0 71.5 6.8 R 25.9SKEWPHOS formate 365 [IrCl(cod)]₂ (R,R)-PTBP- Ammonium IPA 20.4 45.626.8 R 27.8 SKEWPHOS trifluoroacetate 366 [IrCl(cod)]₂ (R,R)-PTBP-Ammonium IPA 31.0 34.7 63.3 R 41.8 SKEWPHOS benzoate 367 [IrCl(cod)]₂(R,R)-PIBP- Ammonium IPA 21.9 26.6 43.3 R 42.0 SKEWPHOS MeO-salicylate368 [IrCl(cod)]₂ (R,R)-PTBP- Ammonium IPA 36.0 10.4 22.2 R 76.0 SKEWPHOSnicotinate *the title compound (containing R-form and S-form)**selectivity (%) = 100 × the title compound (R form + S-form)/(alcoholform + the title compound (R form + S-form))

Examples 369-380 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

The reaction was carried out in the same manner as in Examples 163-368,except that ammonium salicylate (0.155 g) was used as an amine source,[IrCl(cod)]₂ (0.0017 g) was used as a metal source, (R,R)-PTBP-Skewphos(0.0037 g) was used as a ligand, and IPA (1.4 mL) was used as a solvent,and an additive (10 equivalent relative to the iridium catalyst) wasadded to the test tube for the 24-hole autoclave. The selectivity of thetitle compound (containing R-form and S-form) and the enantiomericexcess of the title compound (R-form) were calculated from HPLC underthe same condition as in Examples 163-368. The results are shown inTable 21.

TABLE 21 title compound alcohol Ex. Additive (%)* form (%) % eeselectivity (%)** 369 NH₄Cl 65.3 1.8 65.1 98.2 370 NH₄Br 67.4 1.6 64.297.9 371 BnEt₃NCl 66.6 1.6 66.2 98.4 372 Et₄NBr 66.9 1.8 61.0 97.7 373Et₄NI 63.9 1.6 64.5 98.1 374 LiCl 66.2 1.8 62.3 98.2 375 LiBr•H₂O 68.61.9 58.0 97.5 376 LiI 66.3 1.9 65.5 97.8 377 NaBr 66.0 1.7 60.8 98.0 378Nal 63.3 2.1 61.1 96.5 379 KCl 66.3 2.0 63.2 97.9 380 KBr 66.3 1.7 65.298.3 *the title compound (containing R-form and S-form) **selectivity(%) = 100 × the title compound (R form + S-form)/(alcohol form + thetitle compound (R form + S-form))

Examples 381-385 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(substrate, 0.100 g), ammonium salicylate (0.444 g), [IrCl(cod)]₂(0.0048 g) and (R,R)-PTBP-Skewphos (0.0105 g) were each weighed, andthey were put into an autoclave (120 mL). The atmosphere in theautoclave was decompressed, and the pressure was recovered under argonatmosphere. The procedures were performed five times in total. Underargon atmosphere, dehydrated isopropyl alcohol (4.0 mL) was addedthereto using a syringe, and the mixture was stirred under givenpremixing conditions (temperature and time). After the completion ofstirring, the atmosphere in the autoclave was purged with hydrogen.Hydrogen was fed into the autoclave until 3.0 MPa, and the mixture wasstirred under hydrogen pressure at a given temperature for 20 hr. Afterthe completion of the reaction, the autoclave was cooled, and thehydrogen gas was released. The enantiomeric excess of the title compound(R-form) was calculated from HPLC. The results are shown in Table 22.The HPLC conditions were the same as in Examples 163-368.

TABLE 22 HPLC area % premixing hydrogenation title alcohol Ex.conditions temperature compound (%)* form (%) % ee 381 50° C., 5 h 50°C. 55.5 9.6 71.3 382 50° C., 1 h 50° C. 68.3 6.7 64.9 383 50° C., 2 h50° C. 60.1 7.7 82.1 384 30° C., 5 h 50° C. 71.3 3.5 36.8 385 30° C., 5h 30° C. 27.5 2.0 24.3 *the title compound (containing R-form andS-form)

Examples 386-400 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

The amount of each reactant to be used was as follows.2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.100 g), ammonium salicylate (0.444 g), [IrCl(cod)]₂ (0.0048 g) and(R,R)-PTBP-Skewphos (0.0105 g). The reactants marked with ◯ in Table 23were put into Schlenk flask (10 mL). Separately, the reactants markedwith ⊚ (when exist) were put into another Schlenk flask (10 mL). To eachSchlenk flask containing the reactants was added isopropyl alcohol underargon atmosphere, and each mixture was stirred at a given temperaturefor a given time to prepare the reaction solutions. The reactants notmarked with ◯ nor ⊚ in the table were put into an autoclave (120 mL),the atmosphere in the autoclave was replaced with argon, and thereaction solutions previously heated under stirring were fed thereto.The atmosphere in the autoclave was purged with hydrogen, and hydrogenwas fed into the autoclave until 3.0 MPa, and the mixture was stirredunder hydrogen pressure at a given temperature for 20 hr. After thecompletion of the reaction, the autoclave was cooled, and the hydrogengas was released. The enantiomeric excess of the title compound (R-form)was calculated from HPLC. The results are shown in Table 23. The HPLCconditions were the same as in Examples 163-368. Special procedures weredescribed in the note of Table 23.

TABLE 23 Premix HPLC area % Ammonium temp., hydrogenation title alcoholEx. substrate Salicylate (AS) [IrCl(cod)]₂ ligand time temp. compound *form % ee 386 ◯ ◯ 50° C., 50° C. 60.6 4.0 22.0 5 h 387 ◯ ◯ ◯ 50° C., 50°C. 59.9 3.3 17.8 5 h 388 ◯ ◯ ◯ 50° C., 50° C. 69.0 3.6 39.4 5 h 389 ◯ ◯◯ ◯ 50° C., 50° C. 55.5 9.6 71.3 5 h 390 ◯ ◯ ◯ ◯ 50° C., 50° C. 68.3 6.764.9 1 h 391 ◯ ◯ ◯ ◯ 50° C., 50° C. 60.1 7.7 82.1 2 h 392 ◯ ◯ ◯ ◯ 50°C., 50° C. 61.3 9.5 63.7 2 h 393 ◯ ◯ ◯ ◯ 50° C., 50° C. 54.5 9.2 77.5 2h 394¹⁾ ◯ ◯ 50° C., 50° C. 68.3 3.4 20.2 (+AS 10 eq) 2 h 395²⁾ ◯(+substrate 50° C., 50° C. 60.7 3.5 23.1 (2 eq.), 2 h AS (10 eq.)) 396³⁾◯ ◯ ⊚ ⊚(+substrate 50° C. 50° C. 55.0 2.8 47.2 (2 eq.), 2 h AS (10 eq.))397⁴⁾ ◯ ◯ ⊚ ⊚(rt) 50° C., 50° C. 58.2 3.9 48.0 2 h 398 ◯ ◯ ◯ ◯ 30° C.,50° C. 71.3 3.5 36.8 5 h 399 ◯ ◯ ◯ ◯ 50° C., 30° C. 49.6 16.7 81.9 2 h400 ◯ ◯ ◯ ◯ 30° C., 30° C. 27.5 2.0 24.3 5 h * the title compound(containing R-form and S-form) ¹⁾Ammonium salicylate (10 equivalentrelative to the iridium catalyst) was stirred together with [IrCl(cod)]₂and (R,R)-PTBP-Skewphos (1.1 equivalent relative to the iridiumcatalyst). ²⁾The substrate (2 equivalent relative to the iridiumcatalyst) and ammonium salicylate (10 equivalent relative to the iridiumcatalyst) were stirred together with [IrCl(cod)]₂ and(R,R)-PTU-Skewphos. ³⁾The isopropyl alcohol solution of the substrateand ammonium salicylate, and the isopropyl alcohol solution of[IrCl(Cod)]₂, (R,R)-PTBP-Skewphos, the substrate (2 equivalent relativeto the iridium catalyst) and ammonium salicylate (10 equivalent relativeto the iridium catalyst) were separately put into Schlenk flasks, andeach mixture was stirred at 50° C. for 2 hr. ⁴⁾The isopropyl alcoholsolution of the substrate and ammonium salicylate was stirred at 50° C.for 2 hr, and [IrCl(cod)]₂ and (R,R)-PTBP-Skewphos were stirred at roomtemperature for 2 hr.

Examples 401-412 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

The reaction was carried out in the same manner as in Examples 381-385,except that ammonium salicylate was used in an amount of 5 equivalent(0.222 g) relative to the substrate, and the solvent shown in Table 24was used as a dehydrated solvent used after recovering under argonatmosphere. The selectivity of the title compound (containing R-form andS-form) and the enantiomeric excess of the title compound (R-form) werecalculated from HPLC. The results are shown in Table 24.

TABLE 24 assay yield (%) title alcohol Ex. solvent compound* formselectivity** % ee 401 IPA (10 eq. of AS) 56 10 85.0 68.9 402 IPA (5 eq.of AS) 51 28 65.0 79.6 403 IPA (2 eq. of AS) 39 49 44.0 52.4 404 THF 7410 88.0 74.4 405 MeOH 44 23 66.0 10.7 406 EtOH 60 16 79.0 27.9 407IPA/toluene = 10/1 46 27 63.0 74.9 408 IPA/toluene = 1/1 56 20 74.0 84.4409 THF/toluene = 10/1 71 9 89.0 73.3 410 THF/toluene = 1/1 69 19 78.045.9 411 IPA/H₂O = 10/1 7 31 18.0 13.1 412 THF/H₂O = 10/1 11 32 26.0 9.7*the title compound (containing R-form and S-form) **selectivity (%) =100 × the title compound (R form + S-form)/(alcohol form + the titlecompound (R form + S-form)) AS: Ammonium salicylate

Examples 413-415 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

The reaction was carried out in the same manner as in Examples 401-412,except that the S/C of [IrCl(cod)]₂ was 50 or 100. The results are shownin Table 25.

TABLE 25 assay yield (%) [IrCl(cod)]₂ title alcohol Amine Ex. solvents/c compound * form Ratio** % ee 413 IPA 50 64 9 0.88 37.4 414 THF 50 749 0.89 71.2 415¹⁾ THF 100 80 5 0.94 67.1 ¹⁾The substrate (0.300 g) andammonium salicylate (0.600 g) were used. * the title compound(containing R-form and S-form) **Amine ratio = the title compound (Rform + S-form)/(alcohol form + the title compound (R form + S-form))

Example 416 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

The hydrogenation reaction solution containing2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(2.82 mmol, 59.6% ee) was concentrated under reduced pressure, and theresidue was partitioned between a mixed solvent (30 mL) of toluene/ethylacetate=1/1 and aqueous triethylamine solution (prepared by dilutingtriethylamine (5.26 mL) with water (40 mL)). The organic layer wasseparated, and the aqueous layer was washed twice with a mixed solvent(30 mL) of toluene/ethyl acetate=1/1. The three organic layers werecombined, and washed with aqueous triethylamine solution (prepared bydiluting triethylamine (0.478 mL) with water (40 mL)). The organic layerwas separated, dried over sodium sulfate, and concentrated under reducedpressure. The residue was subjected to solvent replacement withacetonitrile, to the residue were added acetonitrile (27.8 mL) and water(0.96 mL), and the residue was dissolved under heating at 60° C.(S)-Mandelic acid (0.399 g) was added thereto at 60° C., and the mixturewas cooled to room temperature. The resulting crystals were aged at roomtemperature for 3 hr. The crystals were collected by filtration usingHirsch funnel, washed with acetonitrile (4.0 mL), and dried overnightunder reduced pressure at 50° C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (93.4 HPLC area % and 98.9% de). To the obtained wetcrystals was added acetonitrile (72 mL), and the mixture was heatedunder reflux for 30 min, and cooled again to room temperature. Theresulting crystals were collected by filtration using Hirsch funnel,washed with acetonitrile (18 mL), and dried overnight under reducedpressure at 50° C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (1.01 g). yield 77%, 94.4% de.

Example 417 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

The hydrogenation reaction solution containing2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(2.21 mmol, 80.5% ee) was concentrated under reduced pressure, and theresidue was partitioned between a mixed solvent (30 mL) of toluene/ethylacetate=1/1 and aqueous triethylamine solution (prepared by dilutingtriethylamine (5.38 mL) with water (40 mL)). The organic layer wasseparated, and the aqueous layer was washed twice with a mixed solvent(30 mL) of toluene/ethyl acetate=1/1. The three organic layers werecombined, dried over sodium sulfate, and concentrated under reducedpressure. The residue was subjected to solvent replacement withacetonitrile, to the residue were added acetonitrile (22.1 mL) and water(0.76 mL), and the residue was dissolved under heating at 60° C.(S)-Mandelic acid (0.361 g) was added thereto at 60° C., and the mixturewas cooled to room temperature. The resulting crystals were aged at roomtemperature for 3 hr. The crystals were collected by filtration usingHirsch funnel, washed with acetonitrile (4.0 mL), and dried overnightunder reduced pressure at 50° C. to give(R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide(S)-mandelate (93.4 HPLC area % and 98.9% de). To the obtained wetcrystals was added acetonitrile (72 mL), and the mixture was heatedunder reflux for 30 min, and cooled again to room temperature. Theresulting crystals were collected by filtration using Hirsch funnel,washed with acetonitrile (18 mL), and dried overnight under reducedpressure at 50° C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (0.87 g). yield 79%, 97.1% de.

Example 418 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

The hydrogenation reaction solution containing2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(2.79 mmol, 63.6% ee) was concentrated under reduced pressure, and theresidue was partitioned between a mixed solvent (30 mL) of toluene/ethylacetate=1/1 and 1 mol/L aqueous sodium hydroxide solution (40 mL). Theorganic layer was separated, and the aqueous layer was washed twice witha mixed solvent (30 mL) of toluene/ethyl acetate=1/1. The three organiclayers were combined, and washed with 0.1 mol/L aqueous sodium hydroxidesolution (40 mL). The three organic layers were combined, dried oversodium sulfate, and concentrated under reduced pressure. The residue wassubjected to solvent replacement with acetonitrile, to the residue wereadded acetonitrile (22.2 mL) and water (0.77 mL), and the residue wasdissolved under heating at 60° C. (S)-Mandelic acid (0.327 g) was addedthereto at 60° C., and the mixture was cooled to room temperature. Theresulting crystals were aged overnight at room temperature. The crystalswere collected by filtration using Hirsch funnel, washed withacetonitrile (4.0 mL), and dried overnight under reduced pressure at 50°C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (0.81 g). yield 57%, 96.0% de.

Example 419 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

The hydrogenation reaction solution containing2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(2.94 mmol, 64.6% ee) was concentrated under reduced pressure, and theresidue was partitioned between a mixed solvent (30 mL) of toluene/ethylacetate=1/1 and 0.5 mol/L aqueous sodium hydroxide solution (80 mL). Theorganic layer was separated, and the aqueous layer was washed twice witha mixed solvent (30 mL) of toluene/ethyl acetate-1/1. The three organiclayers were combined, and washed with 0.05 mol/L aqueous sodiumhydroxide solution (80 mL). The three organic layers were combined,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was subjected to solvent replacement with acetonitrile, to theresidue were added acetonitrile (27.9 mL) and water (0.96 mL), and theresidue was dissolved under heating at 60° C. (S)-Mandelic acid (0.415g) was added thereto at 60° C., and the mixture was cooled to roomtemperature. The resulting crystals were aged overnight at roomtemperature. The crystals were collected by filtration using Hirschfunnel, washed with acetonitrile (4.0 mL), and dried overnight underreduced pressure at 50° C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (1.04 g). yield 70%, 95.3% de.

Example 420 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(3.50 g), ammonium salicylate (7.76 g), [Ir(cod)₂]BF₄ (0.0248 g) and(R,R)-PTBP-skewphos (0.0366 g) were put into Schlenk flask (200 mL). Theatmosphere in the Schlenk flask was decompressed, and the pressure wasrecovered under argon atmosphere. The procedures were performed fivetimes in total. Under argon atmosphere, super-dehydrated THF (120 mL)was added thereto, and the mixture was stirred at 50° C. for 2 hr. Afterthe completion of stirring, the reaction solution was fed to anautoclave (300 mL) under argon atmosphere. The inside of the Schlenkflask was washed with THF (20 mL), and the washing was also fed to theautoclave. The atmosphere in the autoclave was purged with hydrogen.Hydrogen was fed into the autoclave until 3.0 MPa, and the mixture wasstirred under hydrogen pressure at 50° C. for 2 hr. After the completionof the reaction, the autoclave was cooled, and the hydrogen gas wasreleased. The yields of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamideand the alcohol form, and the enantiomeric excess of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamidewere calculated from HPLC. The production of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(yield 81%, 85% ee) and the alcohol form (2%) was confirmed. Toluene (10mL) was added thereto, and the reaction mixture was concentrated underreduced pressure. To the residue were added a mixed solvent (80 mL) oftoluene/ethyl acetate=1/1 and aqueous ammonia solution (the solution (80mL) prepared by diluting 25% aqueous ammonia solution (7.49 g) withwater), and the mixture was stirred at room temperature for 10 min. Theorganic layer was separated, and the aqueous layer was washed twice witha mixed solvent (20 mL) of toluene/ethyl acetate=1/1. The three organiclayers were combined, and washed with aqueous ammonia solution (thesolution (80 mL) prepared by diluting 25% aqueous ammonia solution (0.68g) with water). The organic layer was separated, dried over sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to solvent replacement with acetonitrile, to the residue wereadded acetonitrile (84 mL) and water (2.9 mL), and the residue wasdissolved under heating at 60° C. (S)-Mandelic acid (1.39 g) was addedthereto at 60° C., and the mixture was cooled to room temperature. Theresulting crystals were aged overnight at room temperature. The crystalswere collected by filtration using Hirsch funnel, washed withacetonitrile (11.6 mL), and dried under reduced pressure at 50° C. for 3hr to give(R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide(S)-mandelate (93.4 HPLC area %, 98.9% de). To the obtained wet crystalswas added acetonitrile (72 mL), and the mixture was heated under refluxfor 30 min, and cooled again to room temperature. The resulting crystalswere collected by filtration using Hirsch funnel, washed withacetonitrile (18 mL), and dried overnight under reduced pressure at 50°C. to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (3.46 g). yield 69%, 99.8% de.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/0.025 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/minretention time: 2.3 min. (the title compound (containing R-form andS-form)), 2.9 min. (alcohol form), 4.8 min. (substrate) conditions forhigh-performance liquid chromatography analysis (optical purity)column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 1.0 mL/mincolumn temperature: 40° C.retention time: 4.6 min. (substrate), 5.8 min. (alcohol form), 11.6 min.(alcohol form), 16.2 min. (the title compound (R-form)), 24.2 min.(enantiomer (S-form) of the title compound).

Examples 421-428 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate, [Ir(cod)₂]BF₄ (0.0028 g) and(R,R)-PTBP-Skewphos (0.0042 g) were each weighed, and they were put intoa test tube for Endeavor (registered trademark). The test tube was setin the apparatus. The atmosphere in the apparatus was decompressed, andthe pressure was recovered under argon atmosphere. The procedures wereperformed five times in total. Under argon atmosphere, super-dehydratedTHF was added thereto using a syringe, and the mixture was stirred at50° C. for 2 hr. After the completion of stirring, the atmosphere in theapparatus was purged with hydrogen. Hydrogen was fed into the apparatusuntil 3.0 MPa, and the mixture was stirred under hydrogen pressure at50° C. for 2 hr. The reaction solution was cooled to room temperature,and the hydrogen gas was released. The yield of each product and theenantiomic excess of the title compound were calculated from HPLC. Theresults are shown in Table 27.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase A: acetonitrile for high-performance liquidchromatography/0.010 mol/L aqueous potassium dihydrogenphosphatesolution=6/4mobile phase B: acetonitrile for high-performance liquidchromatography/0.010 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/mingradient program:

TABLE 26 Mobile phase A Mobile phase B  0.00 min 100% 0%  8.00 min 100%0% 10.00 min  0% 100%  25.00 min  0% 100%  25.01 min 100% 0% 35.00 min100% 0%retention time: 2.2 min. (the title compound (containing R-form andS-form)), 3.6 min. (alcohol form), 7.0 min. (substrate), 19.8 min.(by-product B)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 1.0 mL/mincolumn temperature: 40° C.retention time: 4.6 min. (substrate), 5.8 min. (alcohol form), 11.6 min.(alcohol form), 16.2 min. (the title compound (R-form)), 24.2 min.(enantiomer (S-form) of the title compound).

TABLE 27 HPLC assay (%) amount title compound alcohol form substrateby-product B by-product A total Amine Ex. of AS s/s yield % ee yieldyield yield yield yield ratio* 421 1.2 20 67 83.6 12 1 0 8 96 0.85 4222.0 20 80 73.6 7 0 0 4 95 0.92 423 3.0 20 83 81.9 5 0 0 2 92 0.94 4244.0 20 84 87.2 4 0 0 1 90 0.95 425 1.2 10 66 77.9 14 1 0 4 89 0.83 4262.0 10 71 80.9 9 1 0 2 85 0.89 427 3.0 10 74 80.7 6 1 0 1 83 0.93 4284.0 10 71 76.7 4 1 0 3 82 0.95 *Amine ratio = the title compound (Rform + S-form)/(alcohol form + the title compound (R form + S-form)) AS:Ammonium salicylate

Examples 429-442 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(substrate, 0.400 g), ammonium salicylate, an iridium precursor (0.005equivalent relative to the substrate) and (R,R)-PTBP-Skewphos (0.0042 g)were each weighed, and they were put into a test tube for Endeavor(registered trademark). The test tube was set in the apparatus. Theatmosphere in the apparatus was decompressed, and the pressure wasrecovered under argon atmosphere. The procedures were performed fivetimes in total. Under argon atmosphere, super-dehydrated THF (8.0 mL)was added thereto using a syringe, and the mixture was stirred at 50° C.for 2 hr. After the completion of stirring, the atmosphere in theapparatus was purged with hydrogen. Hydrogen was fed into the apparatusuntil 3.0 MPa, and the mixture was stirred under hydrogen pressure at50° C. for 15 hr. The reaction solution was cooled to room temperature,and the hydrogen gas-was released. The yield of each product and theenantiomic excess of the title compound were calculated from HPLC. Theresults are shown in Table 28. The HPLC conditions were the same as inExamples 421-428.

TABLE 28 HPLC assay (%) title alcohol amount compound form substrateby-product B by-product A total Amine Ex. Ir precursor of AS yield % eeyield yield yield yield yield ratio* 429 [Ir(cod)₂]BF₄ 3.0 57 83.7 3 4 015 94 0.95 430 [Ir(cod)₂]BF₄ 4.0 55 85.1 3 5 0 15 93 0.95 431[IrCl(cod)]₂ 3.0 68 85.2 4 2 0 11 96 0.94 432 [IrCl(cod)]₂ 4.0 73 85.8 42 0 8 95 0.95 433 [IrCl(cod)]₂ + NaBF₄ 3.0 66 84.8 4 3 0 11 95 0.94 434[IrCl(cod)]₂ + NaBF₄ 4.0 65 84.5 3 3 0 11 93 0.96 435 [Ir(cod)₂]BARF 3.073 86.4 5 1 0 8 95 0.94 436 [Ir(cod)₂]BARF 4.0 67 67.9 4 2 0 9 91 0.94437 [IrI(cod)]₂ 3.0 37 84.7 3 10 0 22 94 0.93 438 [IrI(cod)]₂ 4.0 3884.4 3 10 0 20 91 0.93 439 [IrOMe(cod)]₂ 3.0 74 86.5 5 2 0 7 95 0.94 440[IrOMe(cod)]₂ 4.0 71 85.5 4 2 0 8 93 0.95 441 Ir(acac)(cod) 3.0 75 87.25 1 0 6 93 0.94 442 Ir(acac)(cod) 4.0 77 86.9 4 1 0 6 94 0.95 *Amineratio = the title compound (R form + S-form)/(alcohol form + the titlecompound (R form + S-form)) AS: Ammonium salicylate

Examples 443-450 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g), [IrCl(cod)]₂ (0.0019 g) and(R,R)-PTBP-Skewphos (0.0042 g) were each weighed, and they were put intoa test tube for Endeavor (registered trademark). The reaction wascarried out in the same manner as in Examples 421-428. The yield of eachproduct and the enantiomic excess of the title compound were calculatedfrom HPLC. The results are shown in Table 29.

TABLE 29 HPLC assay (%) title alcohol H₂ compound form substrateby-product B by-product A total Amine Ex. pressure temperature yield %ee yield yield yield yield yield ratio* 443 3.0 30 23 95.4 2 15 0 26 920.92 444 3.0 50 73 81.0 3 1 0 7 91 0.96 445 3.0 80 91 37.3 2 0 0 0 930.98 446 3.0 100 81 2.6 3 0 0 0 84 0.96 447 1.0 30 6 94.8 1 36 0 22 870.86 448 1.0 50 34 78.7 1 8 0 23 89 0.97 449 1.0 80 76 16.5 2 0 0 5 880.97 450 1.0 100 54 2.3 3 5 1 13 90 0.95 *Amine ratio = the titleconpound (R form + S-form)/(alcohol form + the title compound (R form +S-form))

Examples 451-457 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g), [IrCl(cod)]₂ (0.0019 g) and(R,R)-PTBP-Skewphos were each weighed, and they were put into a testtube for Endeavor (registered trademark). The reaction was carried outin the same manner as in Examples 421-428. The yield of each product andthe enantiomic excess of the title compound were calculated from HPLC.The results are shown in Table 30.

TABLE 30 HPLC assay (%) title compound alcohol form substrate by-productB by-product A total Amine Ex. ligand/Ir yield % ee yield yield yieldyield yield ratio* 451 0.20 37 78.0 1 7 0 23 91 0.97 452 0.40 72 80.7 21 0 10 95 0.97 453 0.50 77 83.3 3 1 0 7 95 0.96 454 0.80 89 86.5 5 0 0 298 0.95 455 1.10 88 87.1 5 0 0 1 95 0.95 456 2.00 88 85.3 4 0 0 2 960.96 457 3.00 88 87.3 5 0 0 1 95 0.95 *Amine ratio = the title compound(R form + S-form)/(alcohol form + the title compound (R form + S-form))

Examples 458-464 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g), [IrCl(cod)]₂ and(R,R)-PTBP-Skewphos were each weighed, and they were put into a testtube for Endeavor (registered trademark). The reaction was carried outin the same manner as in Examples 421-428. The yield of each product andthe enantiomic excess of the title compound were calculated from HPLC.The results are shown in Table 31.

TABLE 31 HPLC assay (%) title s/c compound alcohol form substrateby-product B by-product A total Amine Ex. (initial) yield % ee yieldyield yield yield yield ratio* 458 5 63 74.3 16 0 0 0 79 0.80 459 10 7384.3 13 0 0 0 86 0.85 460 50 82 89.0 9 0 0 1 93 0.90 461 100 83 89.2 8 00 0 91 0.91 462 200 85 86.7 5 0 0 1 92 0.94 463 400 66 78.8 3 2 0 10 910.96 464 600 33 78.2 1 9 0 23 89 0.97 *Amine ratio = the title compound(R form + S-form)/(alcohol form + the title compound (R form + S-form))

Examples 465-472 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

Catalyst A ([IrCl(cod)]₂ (0.0019 g), (R,R)-PTBP-Skewphos (0.0042 g)) orcatalyst B([IrCl(cod){(R,R)-PTBP-skewphos})] (0.0057 g)), and thereactants marked with ◯ in the table(2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g)) were each weighed, and theyare put into Schlenk flask. The atmosphere in the Schlenk flask wasdecompressed, and the pressure was recovered under argon atmosphere. Theprocedures were performed five times in total. Under argon atmosphere,super-dehydrated THF (8.0 mL) was added thereto using a syringe, and themixture was stirred at 50° C. for 2 hr. Separately, the remainingreactant (not marked with ◯ in the table) was weighed, and put into atest tube for Endeavor (registered trademark), and the atmosphere in theapparatus was replaced with argon. After the completion of stirring, thereaction solution was fed to the Endeavor, and the atmosphere in theapparatus was purged with hydrogen. Hydrogen was fed into the apparatusuntil 3.0 MPa, and the mixture was stirred under hydrogen pressure at50° C. for 2 hr. The reaction solution was cooled to room temperature,and the hydrogen gas was released. The yield of each product and theenantiomic excess of the title compound were calculated from HPLC. Theresults are shown in Table 32. The HPLC conditions were the same as inExamples 421-428. In Example 467, the hydrogenation reaction was carriedout without premixing.

TABLE 32 HPLC assay (%) title alcohol by-product by-product Ammoniumcompound form substrate B A total Amine Ex. catalyst substratesalycylate premix yield % ee yield yield yield yield yield ratio* 465 A○ ○ ○ 88 87.1 5 0 0 1 95 0.95 466 B ○ ○ ○ 84 84.7 4 0 0 2 92 0.95 467 A○ ○ 42 79.2 2 5 0 23 95 0.95 468 B ○ ○ ○ 41 80.2 2 5 0 23 94 0.95 469 A○ ○ 53 76.4 2 4 0 18 95 0.96 470 B ○ ○ 48 77.1 1 4 0 20 93 0.98 471 A ○○ 59 75.5 2 3 0 16 96 0.97 472 B ○ ○ 50 77.0 1 5 0 19 94 0.98 *Amineratio = the title compound (R form + S-form)/(alcohol form + the titlecompound (R form + S-form))

Reference Example 36 Synthesis of Iridium Catalyst

[IrCl(cod){(R,R)-ptbp-skepwhos}] (0.600 g), salicylic acid (0.166 g) andcesium carbonate (0.391 g) were each weighed, and they are put intoSchlenk flask. The atmosphere in the Schlenk flask was decompressed, andthe pressure was recovered under argon atmosphere. The procedures wereperformed five times in total. Under argon atmosphere, super-dehydratedTHF (20.0 mL) and allyl acetate (0.161 mL) were added thereto using asyringe, and the mixture was stirred at room temperature for 10 min, andthen stirred under heating with reflux for 3 hr. The reaction solutionwas cooled to room temperature, dichloromethane (15 mL) was addedthereto, and the mixture was filtered through Celite. The Celite waswashed with dichloromethane (15 mL), and the filtrate and washing wereconcentrated under reduced pressure to give a yellow solid. The solidwas purified by silica gel column chromatography (developingsolvent:hexane/ethyl acetate=10/1) to give a yellow solid (0.65 g).Hexane (15 mL) was added thereto, and the mixture was heated underreflux, ice-cooled, and stirred for 30 min. The resulting solid wasfiltered, and washed with ice-cooled hexane, and the filtrate wasconcentrated under reduced pressure to give the desired compound as amixture of two diastereomers (0.47 g). yield 47%.

³¹P NMR (202 MHz, CDCl₃) δ: −15.58 (d, J=32.3 Hz, 1P), −14.80 (d, J=29.9Hz, 1P), −9.75 (d, J=32.3 Hz, two peaks merge)

Example 473 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g), and the iridium catalyst(0.0059 g) synthesized in Reference Example 36 were each weighed, andthey were put into a test tube for Endeavor (registered trademark). Thetest tube was set in the apparatus. The atmosphere in the apparatus wasdecompressed, and the pressure was recovered under argon atmosphere. Theprocedures were performed five times in total. Under argon atmosphere,super-dehydrated THF (8.0 mL) was added thereto using a syringe, and themixture was stirred at 50° C. for 2 hr. After the completion ofstirring, the atmosphere in the apparatus was purged with hydrogen.Hydrogen was fed into the apparatus until 3.0 MPa, and the mixture wasstirred under hydrogen pressure at 50° C. for 2 hr. The reactionsolution was cooled to room temperature, and the hydrogen gas wasreleased. The yield of each product and the enantiomic excess of thetitle compound were calculated from HPLC. the title compound: yield 84%,85.9% ee; alcohol form: yield 4%; by-product A: yield 0%; by-product Byield 2%.

Examples 474-499 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(substrate) (0.400 g), an ammonium salicylate derivative (amine source,3 equivalent relative to the substrate) and[IrCl(cod){(R,R)-ptbp-Skewphos}] (0.0057 g) were each weighed, and theywere put into a test tube for Endeavor (registered trademark). Thereaction was carried out in the same manner as in Examples 421-428. Theyield of each product and the enantiomic excess of the title compoundwere calculated from HPLC. The results are shown in Table 33.

TABLE 33 HPLC assay (%) title compound alcohol form substrate by-productA total Ex. amine source solvent yield % ee yield yield yield yield 474AS THF 85 83.1 5 0 1 92 475 AS THF/MeOH = 3/1 76 71.8 3 1 6 92 476 ASTHF/IPA = 3/1 86 86.4 5 0 2 95 477 4-ClAS THF 82 87.2 3 1 3 92 4785-ClAS THF 90 88.7 2 0 1 94 479 5-ClAS IPA 22 23.5 2 28 24 100 4805-ClAS IPA/THF = 3/1 77 68.4 3 2 7 96 481 5-ClAS THF/IPA = 3/1 87 86.9 31 3 97 482 5-ClAS THF/MeOH = 3/1 37 72.5 1 11 21 91 483 5-ClAS (1.2 eq.)THF 58 86.2 3 5 14 94 484 5-NO2AS THF 3 61.4 1 72 11 98 485 5-NO2ASTHF/MeOH = 3/1 13 71.5 1 50 17 98 486 5-FAS THF 77 86.1 2 1 4 88 4873-FAS THF 54 50.8 4 6 17 98 488 3-MeAS THF 65 79.9 5 2 11 94 489 3-MeASTHF/MeOH = 3/1 18 69.0 2 9 26 81 490 Ammonium THF 9 95.6 4 48 18 97 491N-acethylanthranate THF/MeOH = 3/1 20 53.8 2 10 28 88 492 4-MeOAS THF 4276.9 8 5 21 97 493 5-MeOAS THF 82 86.5 5 0 1 89 494 5-MeOAS THF/MeOH =3/1 74 73.9 4 1 4 87 495 AHN IPA 0.1 nd 1 79 0 80 496 AHN THF/IPA 0.1 nd1 111 0 112 497 APC IPA 0.1 nd 1 98 0 99 498 APC THF/IPA 0.1 nd 0 97 097 499 ATFA THF 19 77.6 1 64 6 96

Examples 500-508 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate and/or ammonium salt (amine source) and[IrCl(cod){(R,R)-ptbp-Skewphos}] (0.0057 g) were each weighed, and theywere put into a test tube for Endeavor (registered trademark). Thereaction was carried out in the same manner as in Examples 421-428. Theyield of each product and the enantiomic excess of the title compoundwere calculated from HPLC. The results are shown in Table 34.

TABLE 34 Eq of HPLC assay (%) ammonium title compound alcohol formsubstrate by-product A total Ex. amine source salt yield % ee yieldyield yield yield 500 Ammonium 1.2 67 83.6 12 1 8 96 salicylate 501Ammonium 2.0 80 — 7 0 4 95 salicylate 502 Ammonium 3.0 85 83.1 5 0 1 92salicylate 503 Ammonium 1.0/2.0 62 83.6 14 1 10 97 salicylate/ 504Ammonium 2.0/1.0 82 85.3 7 0 2 93 chloride 505 Ammonium 1.0/2.0 58 65.41 2 17 95 salicylate/ 506 Ammonium 2.0/1.0 71 62.4 1 1 9 91 acetate 507Ammonium 1.0/2.0 77 88.2 11 1 3 95 salicylate/ 508 Ammonium 2.0/1.0 8486.6 7 0 2 95 trifluoroacetate

Examples 509-523 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g), [IrCl (cod){(R,R)-ptbp-Skewphos}] (0.0057 g) and additive (amount shown in Table35) were each weighed, and they were put into an autoclave (SUS316, 120mL). The atmosphere in the autoclave was decompressed, and the pressurewas recovered under argon atmosphere. The procedures were performed fivetimes in total. Under argon atmosphere, super-dehydrated THF (8.0 mL)was added thereto using a syringe, and the mixture was stirred at 50° C.for 2 hr. After the completion of stirring, the atmosphere in theautoclave was purged with hydrogen. Hydrogen was fed into the autoclaveuntil 3.0 MPa, and the mixture was stirred under hydrogen pressure at50° C. for 2 hr. After the completion of the reaction, the autoclave wascooled, and the hydrogen gas was released. The yield of each product andthe enantiomic excess of the title compound were calculated from HPLC.The results are shown in Table 35. The HPLC conditions were the same asin Examples 421-428.

TABLE 35 HPLC assay (%) title compound alcohol form substrate by-productA total Ex. Additive eq. yield % ee yield yield yield yield 509(+)-ammmonium ditautrate 0.2 84 26.3 3 0 1 89 510 L-(+)-tautric acid 0.285 19.3 4 0 3 95 511 citric acid 0.2 83 35.3 8 0 1 95 512 18-crown-60.01 80 25.1 3 0 3 89 513 Terpyridine 0.01 86 75.5 3 0 2 93 514Terpyridine 0.01 77 79.7 3 1 4 89 515 Terpyridine 0.02 87 82.4 4 1 1 94516 2,2′-Bipyridine 0.02 74 15.9 2 1 6 89 517 N,N,N′,N′-TETRAMETHYL-0.02 84 27.7 4 0 2 92 1,8-NAPHTHALENEDIAMINE 518 TMEDA 0.02 79 17.3 2 15 92 519 N,N,N′,N″,N″- 0.02 81 21.6 3 0 3 90Pentamethyldiethylenetriamine 520 N-Methyl-N,N-bis(2- 0.02 83 62.1 3 0 290 pyridylmethyl)amine 0.02 87 32.3 3 0 1 92 521 N-tert-Butyl-N,N-bis(2-pyridylmethyl)amine 522 2,6-Bis(N,N- 0.02 81 22.5 3 0 3 90dimetnylaminomethyl)pyridine 523 N2,N2,N6,N6- 0.02 85 27.0 3 0 1 90Tetraethylpyridine-2,6- dicarboxamide

Examples 524-542 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

The following standard reaction was carried out, except that additive(A), solvent (S) or catalyst (C) in the standard reaction was changed asshown in “change column” in Table 36.

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate (0.532 g),[IrCl(cod){(R,R)-ptbp-Skewphos}] (catalyst, 0.0057 g) and an additive(0.2 equivalent relative to the substrate) were each weighed, and theywere put into a test tube for Endeavor (registered trademark). The testtube was set in the apparatus. The atmosphere in the apparatus wasdecompressed, and the pressure was recovered under argon atmosphere. Theprocedures were performed five times in total. Under argon atmosphere,super-dehydrated THF (solvent, 8.0 mL) was added thereto using asyringe, and the mixture was stirred at 50° C. for 2 hr. After thecompletion of stirring, the atmosphere in the apparatus was purged withhydrogen. Hydrogen was fed into the apparatus until 3.0 MPa, and themixture was stirred under hydrogen pressure at 50° C. for 2 hr. Thereaction solution was cooled to room temperature, and the hydrogen gaswas released. The yield of each product and the enantiomic excess of thetitle compound were calculated under the same HPLC conditions as inExamples 421-428. The results are shown in Table 36.

TABLE 36 change A: Additive; HPLC assay (%) S: Solvent; title compoundalcohol form substrate by-product A total Ex. C: catalyst yield % eeyield yield yield yield 524 A: InCl₃ 76 12.5 4 2 9 100 525 A: FeCl₃ 7020.9 3 3 8 92 526 A: ZnCl₂ 88 25.0 5 0 2 97 527 A: LiCl 86 85.6 5 0 1 93528 A: Salicylic 85 82.1 3 1 2 93 acid/Cs₂CO₃ 529 A: Benzophenone 8287.1 5 0 6 99 530 A: Benzaldehyde 44 73.3 2 4 16 82 531 A:Et₃N-salicylic 83 83.7 4 0 3 93 acid 532 A: Et₂NH-salicylic 85 84.9 4 02 93 acid 533 A: Pyridine- <89 87.5 6 0 1 97 disalicylic acid 534 S:THF/Pyridine = 9/1 <79 67.9 2 1 9 100 535 S: THF/Pyridine = 3/1 <64 47.61 3 16 100 536 S: CPME 7 74.4 5 46 21 100 537 S: DME 73 79.4 6 2 8 97538 S: 1,4-Dioxane 88 94.2 2 0 1 99 539 S: t-Amyl alcohol 58 81.3 3 2 1491 540 S: THF/Dioxane = 9/1 83 86.8 3 0 3 92 541 C: [IrOMe(cod)]₂ 6475.1 2 2 12 92 (s/c = 400) 542 C: Ir(acac)(cod) 59 72.5 1 2 13 88 (s/c =400)

Examples 543-565 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(0.400 g), ammonium salicylate, [IrCl(cod)]₂ (0.0019 g) and(R,R)-PTBP-Skewphos (0.0042 g) were each weighed, and they were put intoa test tube for Endeavor (registered trademark). The test tube was setin the apparatus. The atmosphere in the apparatus was decompressed, andthe pressure was recovered under argon atmosphere. The procedures wereperformed five times in total. Under argon atmosphere, super-dehydratedsolvent (4.0 mL) was added thereto using a syringe, and the mixture wasstirred at a given temperature for a given time. After the completion ofstirring, the atmosphere in the apparatus was purged with hydrogen.Hydrogen was fed into the apparatus until 3.0 MPa, and the mixture wasstirred under hydrogen pressure at 50° C. for 2 hr. The reactionsolution was cooled to room temperature, and the hydrogen gas wasreleased. The yield of each product and the enantiomic excess of thetitle compound were calculated from HPLC. The results are shown in Table37. The HPLC conditions were the same as in Examples 421-428.

TABLE 37 Ammmonium HPLC assay (%) Salicylate premix title compoundalcohol form substrate by-product A total Ex. solvent (eq.) temp. time(min) yield % ee yield yield yield yield 543 THF 3.0 25 30 36 65.4 3 720 86 544 THF 3.0 40 30 69 70.3 4 1 10 94 545 THF 3.0 40 60 84 83.7 6 00 90 546 THF 3.0 40 90 85 84.7 6 0 0 91 547 THF 3.0 40 120 85 84.6 6 0 091 548 THF 3.0 40 180 80 85.6 7 0 0 87 549 THF 3.0 50 30 81 79.7 5 0 188 550 THF 3.0 50 45 76 86.6 7 0 0 83 551 THF 3.0 50 60 82 84.2 6 0 0 88552 THF 3.0 50 75 82 85.5 6 0 0 88 553 THF 3.0 50 90 79 85.4 6 0 0 85554 THF 3.0 50 120 74 80.7 6 1 1 83 555 THF 3.0 60 30 77 77.9 5 0 3 88556 THF 3.0 60 60 76 80.8 5 0 1 83 557 dioxane 2.0 25 30 33 87.1 3 11 2597 558 dioxane 2.0 40 30 26 87.2 3 16 28 101 559 dioxane 2.0 50 30 4783.9 4 7 22 102 560 dioxane 2.0 50 60 77 88.1 5 1 7 97 561 dioxane 2.050 90 90 90.6 5 0 1 97 562 dioxane 2.0 50 120 91 90.7 6 0 1 99 563dioxane 2.0 50 180 87 91.3 6 0 1 95 564 dioxane 2.0 60 30 90 92.0 7 0 097 565 dioxane 2.0 60 60 85 91.1 6 0 2 95

Examples 566-576 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂, (R,R)-PTBP-Skewphos,2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, super-dehydratedTHF (200 mL) was fed to the autoclave, and the mixture was stirred at agiven temperature for a given time. After the completion of stirring,the atmosphere in the apparatus was purged ten times with hydrogen. Theatmosphere was pressurized with hydrogen gas, and the mixture wasstirred under a given hydrogen pressure at a given temperature for 24hr. The reaction solution was cooled to room temperature, and thehydrogen gas was released. The yield of each product and the enantiomicexcess of the title compound were calculated from HPLC. The results areshown in Table 38. The HPLC conditions were the same as in Examples421-428.

TABLE 38 HPLC analysis title compound premix Hydrogenation Yield ofalcohol by-product time H₂ time optically form substrate A total Ex. s/ctemp (min.) temp. press. (h) yield % ee active form yield yield yieldyield 566 400 40 90 40 5 24 77 82.1 70 7 0 1 86 567 400 40 90 40 5 24 8086.5 75 7 0 2 91 568 300 40 90 40 5 24 82 88.7 77 8 0 1 92 569 400 40110 40 4 24 74 84.8 68 6 0 4 88 570 400 40 90 40 6 24 81 87.5 76 7 0 190 571 400 35 90 40 5 24 79 82.8 72 5 0 5 94 572 400 45 90 40 5 24 7685.0 70 6 0 3 88 573 400 40 90 35 5 24 72 90.2 68 7 1 5 90 574 400 40 9045 5 24 81 83.1 74 5 0 2 89 575 400 35 90 40 5 40 86 83.0 79 6 0 1 94576 400 35 90 35 5 65 85 84.7 79 7 0 1 94

Examples 577-587 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.0480 g), (R,R)-PTBP-Skewphos (0.1046 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, super-dehydratedTHF (200 mL) and ultrapure water (given ppm) were fed to the autoclave,and the mixture was stirred at a given temperature for a given time.After the completion of stirring, the atmosphere in the apparatus waspurged ten times with hydrogen. The atmosphere was pressurized withhydrogen gas, and the mixture was stirred under a given hydrogenpressure at a given temperature for 24 hr. The reaction solution wascooled to room temperature, and the hydrogen gas was released. The yieldof each product and the enantiomic excess of the title compound werecalculated from HPLC. The results are shown in Table 39. The HPLCconditions were the same as in Examples 421-428.

TABLE 39 HPLC analysis title compound premix Hydrogenation yield ofalcohol by-product water time H₂ time optically form substrate A totalEx. (ppm) temp (min.) temp. press. (h) yield % ee active form yieldyield yield yield 577 100 40 90 40 5 24 80 86.4 75 7 0 2 92 578 1000 4090 40 5 24 83 86.1 77 7 0 2 94 579 2000 40 90 40 5 24 84 86.2 78 7 0 397 580 3000 40 90 40 5 24 83 83.2 76 7 1 4 99 581 4000 40 90 40 5 24 7882.0 71 6 1 7 99 582 8000 40 90 40 5 24 54 73.3 47 6 6 18 102 583 2000rt 10 40 5 24 12 nd nd 2 24 29 96 584 2000 40 90 40 5 40 89 83.7 82 8 01 98 585 2000 40 90 40 5 30 86 85.9 80 7 0 1 96 586 2000 40 90 40 5 4089 84.2 82 7 0 1 97 587 2000 rt 10 40 5 24 82 86.4 76 7 0 2 93

Example 588 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.0480 g), (R,R)-PTBP-Skewphos (0.1046 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, deoxygenated THF(200 mL) was fed to the autoclave, and the mixture was stirred at 40° C.for 90 min. After the completion of stirring, the atmosphere in theapparatus was purged ten times with hydrogen. The atmosphere waspressurized with hydrogen gas, and the mixture was stirred at 5.0 MPa at40° C. for 24 hr. The reaction solution was cooled to room temperature,and the hydrogen gas was released. The yield of each product and theenantiomic excess of the title compound were calculated from HPLC. thetitle compound: yield 81%, 87.1% ee; alcohol form: yield 7%; by-productA: yield 2%.

Conditions for High-Performance Liquid Chromatography Analysis (AreaNormalization)

column: YMC-Pack ODS-A (manufactured by YMC. CO., LTD.), 4.6*150 mmUV detection wavelength: 254 nmmobile phase A: acetonitrile for high-performance liquidchromatography/0.010 mol/L aqueous potassium dihydrogenphosphatesolution=6/4mobile phase B: acetonitrile for high-performance liquidchromatography/0.010 mol/L aqueous potassium dihydrogenphosphatesolution=8/2flow rate: 1.0 mL/mingradient program:

TABLE 40 Mobile phase A Mobile phase B  0.00 min 100% 0%  8.00 min 100%0% 10.00 min  0% 100%  25.00 min  0% 100%  25.01 min 100% 0% 35.00 min100% 0%retention time: 2.2 min. (the title compound (containing R-form andS-form)), 3.6 min. (alcohol form), 7.0 min. (substrate), 19.8 min.(by-product B)

Conditions for High-Performance Liquid Chromatography Analysis (OpticalPurity)

column: IA (manufactured by Daicel Chemical Industries), 4.6*250 mmUV detection wavelength: 254 nmmobile phase: acetonitrile for high-performance liquidchromatography/methanol/water=80/15/5flow rate: 1.0 mL/mincolumn temperature: 40° C.retention time: 4.6 min. (substrate), 5.8 min. (alcohol form), 11.6 min.(alcohol form), 16.2 min. (the title compound (R-form)), 24.2 min.(enantiomer (S-form) of the title compound).

Example 589 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.0480 g), (R,R)-PTBP-Skewphos (0.1046 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, air-saturatedTHF (200 mL) was fed to the autoclave, and the mixture was stirred at40° C. for 90 min. After the completion of stirring, the atmosphere inthe apparatus was purged ten times with hydrogen. The atmosphere waspressurized with hydrogen gas, and the mixture was stirred at 5.0 MPa at40° C. for 24 hr. The reaction solution was cooled to room temperature,and the hydrogen gas was released. The yield of each product and theenantiomic excess of the title compound were calculated from HPLC. thetitle compound: yield 72%, 82.2% ee; alcohol form: yield 5%; by-productA: yield 7%.

The HPLC conditions were the same as in Example 588.

Example 590 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.0480 g), (R,R)-PTBP-Skewphos (0.1046 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under dry air. The procedures were performedseven times in total. Under dry air, super-dehydrated THF (200 mL) wasfed to the autoclave, and the mixture was stirred at 40° C. for 90 min.After the completion of stirring, the atmosphere in the apparatus waspurged ten times with hydrogen. The atmosphere was pressurized withhydrogen gas, and the mixture was stirred at 5.0 MPa at 40° C. for 24hr. The reaction solution was cooled to room temperature, and thehydrogen gas was released. The yield of each product and the enantiomicexcess of the title compound were calculated from HPLC. the titlecompound: yield 6%; alcohol form: yield 1%; by-product A: yield 23%.

The HPLC conditions were the same as in Example 588.

Example 591 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.0480 g), (R,R)-PTBP-Skewphos (0.1046 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(20.00 g) and ammonium salicylate (26.62 g) were put into an autoclave(1 L). The atmosphere in the apparatus was purged ten times withnitrogen. Under nitrogen atmosphere, super-dehydrated THF (200 mL) wasfed to the autoclave, and the mixture was stirred at 40° C. for 90 min.After the completion of stirring, the atmosphere in the apparatus waspurged ten times with hydrogen. The atmosphere was pressurized withhydrogen gas, and the mixture was stirred at 5.0 MPa at 40° C. for 24hr. The reaction solution was cooled to room temperature, and thehydrogen gas was released. The yield of each product and the enantiomicexcess of the title compound were calculated from HPLC. the titlecompound: yield 78%, 85.3% ee; alcohol form: yield 6%; by-product A:yield 3%. The HPLC conditions were the same as in Example 588.

Example 592 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.1985 g), (R,R)-PTBP-Skewphos (0.4322 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(62.00 g) and ammonium salicylate (82.52 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, super-dehydratedTHF (620 mL) and ultrapure water (1.10 mL) were fed to the autoclave,and the mixture was stirred at 40° C. for 90 min. After the completionof stirring, the atmosphere in the apparatus was purged ten times withhydrogen. The atmosphere was pressurized with hydrogen gas, and themixture was stirred at 4.9 MPa at 40° C. for 40 hr. After 40 hr, thehydrogen pressure decreased to 3.0 MPa. The reaction solution was cooledto room temperature, and the hydrogen gas was released. The yield ofeach product and the enantiomic excess of the title compound werecalculated from HPLC. the title compound: yield 87%, 82.2% ee; alcoholform: yield 7%; by-product A: yield 1%.

The HPLC conditions were the same as in Example 588.

Example 593 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

[IrCl(cod)]₂ (0.1489 g), (R,R)-PTBP-Skewphos (0.3242 g),2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(62.00 g) and ammonium salicylate (82.52 g) were put into an autoclave(1 L). The atmosphere in the apparatus was decompressed, and thepressure was recovered under argon atmosphere. The procedures wereperformed seven times in total. Under argon atmosphere, super-dehydratedTHF (620 mL) and ultrapure water (1.10 mL) were fed to the autoclave,and the mixture was stirred at 40° C. for 90 min. After the completionof stirring, the atmosphere in the apparatus was purged ten times withhydrogen. The atmosphere was pressurized with hydrogen gas, and themixture was stirred at a constant pressure of 5.5 MPa at 40° C. for 40hr. The reaction solution was cooled to room temperature, and thehydrogen gas was released. The yield of each product and the enantiomicexcess of the title compound were calculated from HPLC. the titlecompound: yield 86%, 85.2% ee; alcohol form: yield 7%; by-product A:yield 1%.

The HPLC conditions were the same as in Example 588.

Example 594 Synthesis of2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(200.00 g), ammonium salicylate (266.18 g), [IrCl(cod)]₂ (1.92 g) and(R,R)-PTBP-skewphos (4.18 g) were put into anautoclave (10 L). Theatmosphere in the autoclave was decompressed, and the pressure wasrecovered under argon atmosphere. The procedures were performed seventimes in total. Under argon atmosphere, super-dehydrated THF (4.00 L)was added thereto, and the mixture was stirred at 45-52° C. for 2 hr.After the completion of stirring, the atmosphere in the autoclave waspurged ten times with hydrogen. Hydrogen was fed into the autoclaveuntil 1.02 MPa, and the mixture was stirred under hydrogen pressure at52-55° C. for 19 hr. After the completion of the reaction, the autoclavewas cooled to 31° C., and the hydrogen gas was released. The yield andenantiomeric excess of the title compound were calculated from HPLC. Theproduction of the title compound (yield 86%, 84.4% ee) was confirmed.The reaction mixture was concentrated under reduced pressure to 1.0 L,toluene (8.0 L) was added thereto, and the reaction mixture wasconcentrated under reduced pressure to 1.6 L. To the residue were addedethyl acetate (4.0 L) and aqueous ammonia solution (the solution (1.6 L)prepared by diluting 25% aqueous ammonia solution (260 g) with water),and the mixture was stirred at room temperature for 10 min. The aqueouslayer was removed, and to the organic layer was added aqueous ammoniasolution (the solution (1.6 L) prepared by diluting 25% aqueous ammoniasolution (40 g) with water), and the mixture was stirred at roomtemperature for 10 min. The aqueous layer was removed, and the organiclayer was concentrated under reduced pressure to 1.0 L. Acetonitrile(1.0 L) was added thereto, and the mixture was concentrated underreduced pressure to 1.0 L. The procedures were performed twice in total.The residue was put into a reaction container (10 L), and acetonitrile(4.8 L) and water (0.2 L) were added thereto. The mixture was heated to60° C., (S)-mandelic acid (87.01 g) was added thereto at 60° C., and themixture was cooled to room temperature over 3 hr. The resulting crystalswere collected by filtration using a glass filter, washed withacetonitrile (1.6 L), and dried under reduced pressure at 50° C. toconstant weight to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(S)-mandelate (193.93 g, yield 67.4%). The obtained crystal (190 g) andsodium hydrogencarbonate (63.45 g) were put into a reaction container (3L). Water (1.44 L) and acetonitrile (1.44 L) were added thereto, and themixture was stirred at 11-22° C. for 2 hr. Activated carbon (5.70 g) wasadded thereto, and the mixture was stirred at room temperature for 10min. The reaction mixture was filtered through a membrane filter (45μm), and the filter was washed with a mixed solvent (190 mL) ofacetonitrile/water=1/1. The filtrate and washing were put into areaction container (10 L), and water (3.23 L) was added dropwise at13-18° C. The resulting crystals were aged at room temperature for 3 hr.The crystals were collected by filtration using Hirsch funnel, andwashed with water (1.9 L). The obtained crystals were dried underreduced pressure at 50° C. to constant weight to give2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide(128.24 g, yield 97%). HPLC 96.8 area %, 98.3% ee. The HPLC conditionswere the same as in Example 588.

INDUSTRIAL APPLICABILITY

According to the present invention, compound (III) or a salt thereof,which is a key intermediate, can be produced with good optical purity ingood yield, by subjecting compound (I) or a salt thereof to anasymmetric reduction reaction, followed by deprotection. Particularly,after the deprotection, by crystallization of the diastereomer salt withoptically active di-p-toluoyl-tartaric acid or optically active mandelicacid, the salt of compound (III) can be produced with better opticalpurity. Therefore, the objective compound (V) or a salt thereof can beproduced on an industrial scale.

This application is based on patent application No. 2017-106280 filed onMay 30, 2017 in Japan, the contents of which are encompassed in fullherein.

The invention claimed is:
 1. A method of producing an optically activeform of a compound represented by the following formula (II):

wherein R¹ is a C₁₋₆ alkyl group; R² is a hydrogen atom or a halogenatom; R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkylgroup; PG is a protecting group; and the carbon atom marked with * is anasymmetric carbon atom, or a salt thereof, which comprises subjecting acompound represented b the following formula (I):

wherein each symbol is as defined above, or a salt thereof, to anasymmetric reduction reaction.
 2. A method of producing an opticallyactive form of a compound represented by the following formula (V):

wherein R¹ is a C₁₋₆ alkyl group; R² is a hydrogen atom or a halogenatom; R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkylgroup; R⁴ and R⁵ are each independently a hydrogen atom, a halogen atom,a cyano group, a nitro group, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an acyl group, anoptionally substituted amino group, an optionally substituted carbamoylgroup, an optionally substituted thiocarbamoyl group, an optionallysubstituted sulfamoyl group, an optionally substituted hydroxy group, anoptionally substituted sulfanyl (SH) group, or an optionally substitutedsilyl group; and the carbon atom marked with * is an asymmetric carbonatom, or a salt thereof, which comprises a step of subjecting a compoundrepresented by the following formula (I);

wherein PG is a protecting group, and and the other symbols are asdefined above, or a salt thereof, to an asymmetric reduction reaction toobtain an optically active form of a compound represented by thefollowing formula II;

wherein each symbol is as defined above, or a salt thereof.
 3. Themethod of claim 2, which further comprises a step of subjecting anoptically active form of a compound represented by the following formula(II);

wherein R¹ is a C₁₋₆ alkyl group; R² is a hydrogen atom or a halogenatom; R³ is a hydrogen atom or an optionally halogenated C₁₋₆ alkylgroup; PG is a protecting group; and the carbon atom marked with * is anasymmetric carbon atom, or a salt thereof, to a deprotection reaction,and a step of reacting the obtained optically active form of a compoundrepresented by the following formula (III);

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the following formula (IV);

wherein X is a leaving group; and R⁴ and R⁵ are each independently ahydrogen atom, a halogen atom, a cyano group, a nitro group, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an acyl group, an optionally substituted aminogroup, an optionally substituted carbamoyl group, an optionallysubstituted thiocarbamoyl group, an optionally substituted sulfamoylgroup, an optionally substituted hydroxy group, an optionallysubstituted sulfanyl (SH) group, or an optionally substituted silylgroup, or a salt thereof.
 4. The method of claim 3, wherein theoptically active form of the compound represented by the formula (III)or a salt thereof is a salt of the optically active form of the compoundrepresented by the formula (III) with mandelic acid.
 5. The method ofclaim 3, wherein X is a hydroxy group.
 6. The method of claim 1, whereinthe asymmetric reduction reaction is an asymmetric hydrogenationreaction in the presence of a transition metal complex.
 7. The method ofclaim 6, wherein the transition metal complex is an iridium complex. 8.The method of claim 1, wherein PG is represented by the followingformula (VI):

wherein Ar¹ is a hydrogen atom or an optionally substituted C₆₋₁₄ arylgroup; and Ar² is an optionally substituted C₆₋₁₄ aryl group.
 9. Themethod of claim 8, wherein Ar¹ and Ar² are each independently anoptionally substituted phenyl group.
 10. A compound represented y thefollowing formula (VII):

wherein Ar³ and Ar are each independently an optionally substitutedC₆₋₁₄ aryl group, or a salt thereof.
 11. An optically active form of acompound represented by the following formula (VIII):

wherein Ar⁵ and Ar⁶ are each independently an optionally substitutedC₆₋₁₄ aryl group, and the carbon atom marked with * is an asymmetriccarbon atom, or a salt thereof.